University of Groningen Therapeutic drug monitoring Pranger, Anna Diewerke

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Therapeutic drug monitoring

Pranger, Anna Diewerke

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2018

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Pranger, A. D. (2018). Therapeutic drug monitoring: How to improve moxifloxacin exposure in tuberculosis

patients. Rijksuniversiteit Groningen.

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2A

Chapter

Fluoroquinolones,

the cornerstone of treatment of

drug-resistant tuberculosis:

a pharmacokinetic and

pharmacodynamic approach

A.D. Pranger, J.W.C. Alffenaar, and R.E. Aarnoutse

Current Pharmeutical Design 2011;17(27):2900-2930

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Abstract

Fluoroquinolones (FQs) are important drugs to treat drug-resistant tuberculosis. In this review we integrated pharmacokinetic properties (PK) and microbiological susceptibility against M. tuberculosis and eventually evaluated the pharmcodynamic (PD) properties, as well as the influence of co-administered agents on these characteristics, for the currently used FQs (ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin and moxifloxacin) in TB treatment. Future FQs that are being developed may overcome the problems with FQs that are used in daily practice. Therefore PK and pharmacodynamic (PD) properties of novel FQs (clinafloxacin, garenoxacin, lomefloxacin, sitafloxacin, sparfloxacin, trovafloxacin, gemifloxacin, grepafloxacin and DC-159a) were evaluated in TB treatment as well. Integrating both excellent PK and PD properties, moxifloxacin, possibly at a higher dosage, may fulfil a far more important role in the treatment of multi-drug and early-generation FQ resistant TB than proposed in the current WHO guideline. Sparfloxacin, trovafloxacin and sitafloxacin are upcoming novel FQs that may be useful for drug-resistant TB based on their favourable PK properties or microbiological susceptibility against M. tuberculosis. Finally, the 8-methoxy moiety, as present in the chemical structure of MFX, will possibly provide DC-159a with promising PK/PD characteristics and consequently this FQ may develop into a key FQ in future drug-resistant TB treatment.

Introduction

The global extent in multidrug resistant tuberculosis (MDR-TB) cases is very alarming (1-6). The proportion of MDR-TB among new TB cases has nearly tripled to about 3% since 2004, with high rates up to 22% in certain countries (7). In addition, it should be recognized that rates of MDR-TB could become even 4-fold higher than currently assumed, if new susceptibility breakpoints for first-line TB drugs were used, based on current pharmacokinetic/pharmacodynamic science and variability in exposure to these drugs (8). Fluoroquinolones (FQs) are key players in the field of MDR-TB treatment (1;9). Unfortunately, FQ resistance or “pre-extensively drug resistant TB” is upcoming and reported worldwide for ciprofloxacin (CFX), levofloxacin (LFX), moxifloxacin (MFX) and particularly for ofloxacin (OFX) (2;4;6;10-30), but a lack of resistance have been reported for aforementioned agents as well (19;31-38). Furthermore, extensively drug-resistant tuberculosis (XDR-TB), is becoming more of a global health concern, predominantly due to inadequate management of MDR-TB (1;2;12;15;17;23;25;39-45).

In daily practice, there are several guidelines and publications on how to manage drug-resistant TB (1;15). According to the current WHO guideline (46), TB drugs are divided into five groups to be of help for a practicing physician to make a choice for the right drug. MDR-TB treatment regimens should be designed with a systematic approach based on a hierarchy in these groups. Together with injectable TB drugs (i.e. group 2), FQs (i.e. designated as group 3) are considered to be the cornerstone of MDR-TB regimens. The further classification of FQs in generations is based on integration of both microbiological susceptibilities and pharmacokinetic (PK) data (47). Drugs that are active against M.

tuberculosis belong to the second (CFX and OFX), third (LFX and GFX) and fourth

generation (MFX) of FQs. According to the current WHO guidelines for programmatic management of drug-resistant tuberculosis, CFX should be no longer part of an MDR-TB regimen as time to achieve sputum conversion will prolong and the relapse rate will increase (46;48). Despite its moderate anti-mycobacterial activity, the low cost drug OFX is still widely used in resource-limited countries (41;46). OFX resistance seems therefore not surprising. Instead, a later-generation FQ (i.e. LFX) is recommended in the drug-resistant regimen. MFX is not yet recommended by the WHO, with the argument that there is insufficient data to substantiate its long-term safety. GFX should only be used as last remedy, in case there is no other later-generation FQ available (46). In this period of emerging FQ resistance, novel FQs are needed for future drug-resistant TB regimens. Based on their molecular structure, the new FQs, sitafloxacin (STX), sparfloxacin (SFX) and clinafloxacin (CLX) are suggested to be highly active, in contrast to grepafloxacin (GPX), gemifloxacin (GMX), trovafloxacin (TFX)

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Chapter

2

a

Abstract

Fluoroquinolones (FQs) are important drugs to treat drug-resistant tuberculosis. In this review we integrated pharmacokinetic properties (PK) and microbiological susceptibility against M. tuberculosis and eventually evaluated the pharmcodynamic (PD) properties, as well as the influence of co-administered agents on these characteristics, for the currently used FQs (ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin and moxifloxacin) in TB treatment. Future FQs that are being developed may overcome the problems with FQs that are used in daily practice. Therefore PK and pharmacodynamic (PD) properties of novel FQs (clinafloxacin, garenoxacin, lomefloxacin, sitafloxacin, sparfloxacin, trovafloxacin, gemifloxacin, grepafloxacin and DC-159a) were evaluated in TB treatment as well. Integrating both excellent PK and PD properties, moxifloxacin, possibly at a higher dosage, may fulfil a far more important role in the treatment of multi-drug and early-generation FQ resistant TB than proposed in the current WHO guideline. Sparfloxacin, trovafloxacin and sitafloxacin are upcoming novel FQs that may be useful for drug-resistant TB based on their favourable PK properties or microbiological susceptibility against M. tuberculosis. Finally, the 8-methoxy moiety, as present in the chemical structure of MFX, will possibly provide DC-159a with promising PK/PD characteristics and consequently this FQ may develop into a key FQ in future drug-resistant TB treatment.

Introduction

The global extent in multidrug resistant tuberculosis (MDR-TB) cases is very alarming (1-6). The proportion of MDR-TB among new TB cases has nearly tripled to about 3% since 2004, with high rates up to 22% in certain countries (7). In addition, it should be recognized that rates of MDR-TB could become even 4-fold higher than currently assumed, if new susceptibility breakpoints for first-line TB drugs were used, based on current pharmacokinetic/pharmacodynamic science and variability in exposure to these drugs (8). Fluoroquinolones (FQs) are key players in the field of MDR-TB treatment (1;9). Unfortunately, FQ resistance or “pre-extensively drug resistant TB” is upcoming and reported worldwide for ciprofloxacin (CFX), levofloxacin (LFX), moxifloxacin (MFX) and particularly for ofloxacin (OFX) (2;4;6;10-30), but a lack of resistance have been reported for aforementioned agents as well (19;31-38). Furthermore, extensively drug-resistant tuberculosis (XDR-TB), is becoming more of a global health concern, predominantly due to inadequate management of MDR-TB (1;2;12;15;17;23;25;39-45).

In daily practice, there are several guidelines and publications on how to manage drug-resistant TB (1;15). According to the current WHO guideline (46), TB drugs are divided into five groups to be of help for a practicing physician to make a choice for the right drug. MDR-TB treatment regimens should be designed with a systematic approach based on a hierarchy in these groups. Together with injectable TB drugs (i.e. group 2), FQs (i.e. designated as group 3) are considered to be the cornerstone of MDR-TB regimens. The further classification of FQs in generations is based on integration of both microbiological susceptibilities and pharmacokinetic (PK) data (47). Drugs that are active against M.

tuberculosis belong to the second (CFX and OFX), third (LFX and GFX) and fourth

generation (MFX) of FQs. According to the current WHO guidelines for programmatic management of drug-resistant tuberculosis, CFX should be no longer part of an MDR-TB regimen as time to achieve sputum conversion will prolong and the relapse rate will increase (46;48). Despite its moderate anti-mycobacterial activity, the low cost drug OFX is still widely used in resource-limited countries (41;46). OFX resistance seems therefore not surprising. Instead, a later-generation FQ (i.e. LFX) is recommended in the drug-resistant regimen. MFX is not yet recommended by the WHO, with the argument that there is insufficient data to substantiate its long-term safety. GFX should only be used as last remedy, in case there is no other later-generation FQ available (46). In this period of emerging FQ resistance, novel FQs are needed for future drug-resistant TB regimens. Based on their molecular structure, the new FQs, sitafloxacin (STX), sparfloxacin (SFX) and clinafloxacin (CLX) are suggested to be highly active, in contrast to grepafloxacin (GPX), gemifloxacin (GMX), trovafloxacin (TFX)

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and garenoxacin (GNX) which appear to be moderately active against M. tuberculosis DNA gyrase (49). Therefore, FQs that are promising for future TB treatment may help to overcome the resistance against currently important key FQs.

Despite favourable microbiological and/or pharmacokinetic properties for treatment of (drug-resistant) tuberculosis, most of the FQs are not marketed agents for treatment of tuberculosis. A summary of the currently registered indications and of the clinical

development state for TB treatment of the currently used and novel FQs is shown in Table 1.

The aim of this review is to integrate available data on pharmacokinetic (PK) properties with reported microbiological susceptibility against (drug-resistant) M. tuberculosis and eventually to evaluate the pharmacodynamic (PD) parameters, as well as the influence of co-administered agents on both PK and PD characteristics, of currently used and novel FQs in the treatment of drug-resistant TB. Based on available data, it seems prudent to revise or expand the treatment criteria and consider other FQs to be one of the cornerstone drugs in the drug-resistant TB regimen. In addition, this review indentifies FQs for which more clinical research is required along with the need to revise the current state of affaires on the market of some FQs. Table 1 (I) . S ta te of c lini ca l de vel op m en t i n T B tre atm en t a nd g en era l m ar keti ng s tatu s. FQ Ma rk eti ng s tat us oth er t ha n TB 1,7 Regi st ered str en gth (m g) Regi st ered i nd ic at ion 2, 7 Cl ini ca l de vel op m en t stat us for T B trea tm en t 3 Ref erenc es S ec on d g en erat io n CF X (Ci pro®) Ap pr ov ed 100 – 75 0 (c om pl ic ate d) 4 urin ar y trac t i nf ec tion s, py el one ph rit is 4 , ac ute u nc om pl ic ate d c ys tit is , c hroni c ba ct eria l pros tat iti s, l ow er r es pi rato ry trac t i nf ec tio ns , a cut e si nu si tis , S SS I, b on e an d j oi nt inf ec tio ns , c om pl ic ate d intra -a bd om ina l i nf ec tion s, i nf ec tiou s d iarr he a, t yph oi d fev er, unc om pl ic at ed c er vi cal a nd urethra l g on orr ha, inh al ati ona l a nth rax 5 None (408 ) O FX Ap pr ov ed 200 – 40 0 Unk no w n Pha se II (20 8;4 08 ) Thi rd g en er ati on G FX Di sc on tinu ed 8 Unk no w n Unk no w n Pha se III (20 8;4 08 ) LFX (Le va qu in® ) Ap pr ov ed 250 - 7 50 Pne um on ia (nos oc om ial an d c om m un ity ac qu ired ), ac ute b ac teri ca l s in us iti s, a cute ba ct eric al ex ac erba tio n or c hroni c br on chi tis , (u n)c om pl ic ate d SS SI, c hr on ic ba cter ia l pros tat iti s, (u n)c om pl ic ate d u rina ry trac t inf ec tion s, ac ute p ye lon eph riti s, i nh al ati ona l an thrax Pha se III 6 /IV 6 (40 8;4 09 ) 1 The m ar keti ng s tat us is ind ic ate d as the s tat e of the F Q on the m ar ket of the Uni te d Sta tes an d or Euro pe an Uni on ; 2 In di cat ed in ad ul ts ( at lea st 18 y ears ) inf ec ted wi th s us cep tib le m ic ro organ is m s un les s in di cate d oth erw is e; 3 The c lin ic al de ve lo pm en t s tat us w as ind ic at ed as “no ne ” whe n no Ph as e I t o IV c lini ca l trai l r eg is tered on c lini ca ltr ial s.go v or av ai lab le as li ter atu re on P ubm ed ; 4 In c hi ldren; 5 In adu lts a nd c hi ldren; 6 Mu lti drug res is tan t tu be rc ul os is ; 7 The m ar keti ng stat us an d/ or the r eg is tere d ind ic at ion w as ind ic ate d as “ un kno w n” w he n reg is te red da ta was no t a va ila bl e on fda .go v or em ea .eu rop e.e u; 8 D is con tinu ati on du e t o c on si de rat io n o f c om m er ci al po te nti al ; FQ = fl uoroqu ino lo ne , T B = tu be rc ul os is , n .a. = n ot app lic ab le, SS SI = s ki n a nd s ki n s truc ture i nf ec tion s.

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Chapter

2

a

and garenoxacin (GNX) which appear to be moderately active against M. tuberculosis DNA gyrase (49). Therefore, FQs that are promising for future TB treatment may help to overcome the resistance against currently important key FQs.

Despite favourable microbiological and/or pharmacokinetic properties for treatment of (drug-resistant) tuberculosis, most of the FQs are not marketed agents for treatment of tuberculosis. A summary of the currently registered indications and of the clinical

development state for TB treatment of the currently used and novel FQs is shown in Table 1.

The aim of this review is to integrate available data on pharmacokinetic (PK) properties with reported microbiological susceptibility against (drug-resistant) M. tuberculosis and eventually to evaluate the pharmacodynamic (PD) parameters, as well as the influence of co-administered agents on both PK and PD characteristics, of currently used and novel FQs in the treatment of drug-resistant TB. Based on available data, it seems prudent to revise or expand the treatment criteria and consider other FQs to be one of the cornerstone drugs in the drug-resistant TB regimen. In addition, this review indentifies FQs for which more clinical research is required along with the need to revise the current state of affaires on the market of some FQs. Table 1 (I) . S ta te of c lini ca l de vel op m en t i n T B tre atm en t a nd g en era l m ar keti ng s tatu s. FQ Ma rk eti ng s tat us oth er t ha n TB 1,7 Regi st ered str en gth (m g) Regi st ered i nd ic at ion 2, 7 Cl ini ca l de vel op m en t stat us for T B trea tm en t 3 Ref erenc es S ec on d g en erat io n CF X (Ci pro®) Ap pr ov ed 100 – 75 0 (c om pl ic ate d) 4 urin ar y trac t i nf ec tion s, py el one ph rit is 4 , ac ute u nc om pl ic ate d c ys tit is , c hroni c ba ct eria l pros tat iti s, l ow er r es pi rato ry trac t i nf ec tio ns , a cut e si nu si tis , S SS I, b on e an d j oi nt inf ec tio ns , c om pl ic ate d intra -a bd om ina l i nf ec tion s, i nf ec tiou s d iarr he a, t yph oi d fev er, unc om pl ic at ed c er vi cal a nd urethra l g on orr ha, inh al ati ona l a nth rax 5 None (408 ) O FX Ap pr ov ed 200 – 40 0 Unk no w n Pha se II (20 8;4 08 ) Thi rd g en er ati on G FX Di sc on tinu ed 8 Unk no w n Unk no w n Pha se III (20 8;4 08 ) LFX (Le va qu in® ) Ap pr ov ed 250 - 7 50 Pne um on ia (nos oc om ial an d c om m un ity ac qu ired ), ac ute b ac teri ca l s in us iti s, a cute ba ct eric al ex ac erba tio n or c hroni c br on chi tis , (u n)c om pl ic ate d SS SI, c hr on ic ba cter ia l pros tat iti s, (u n)c om pl ic ate d u rina ry trac t inf ec tion s, ac ute p ye lon eph riti s, i nh al ati ona l an thrax Pha se III 6 /IV 6 (40 8;4 09 ) 1 The m ar keti ng s tat us is ind ic ate d as the s tat e of the F Q on the m ar ket of the Uni te d Sta tes an d or Euro pe an Uni on ; 2 In di cat ed in ad ul ts ( at lea st 18 y ears ) inf ec ted wi th s us cep tib le m ic ro organ is m s un les s in di cate d oth erw is e; 3 The c lin ic al de ve lo pm en t s tat us w as ind ic at ed as “no ne ” whe n no Ph as e I t o IV c lini ca l trai l r eg is tered on c lini ca ltr ial s.go v or av ai lab le as li ter atu re on P ubm ed ; 4 In c hi ldren; 5 In adu lts a nd c hi ldren; 6 Mu lti drug res is tan t tu be rc ul os is ; 7 The m ar keti ng stat us an d/ or the r eg is tere d ind ic at ion w as ind ic ate d as “ un kno w n” w he n reg is te red da ta was no t a va ila bl e on fda .go v or em ea .eu rop e.e u; 8 D is con tinu ati on du e t o c on si de rat io n o f c om m er ci al po te nti al ; FQ = fl uoroqu ino lo ne , T B = tu be rc ul os is , n .a. = n ot app lic ab le, SS SI = s ki n a nd s ki n s truc ture i nf ec tion s.

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Table 1 (II) . S tate of c lini ca l de vel op m en t i n T B treatm en t a nd ge neral m ark eti ng s tat us . FQ Ma rk eti ng s tat us oth er t ha n T B 1,7 Reg is tered str en gth (m g) Regi st ered i nd ic at ion 2, 7 Cl ini ca l de vel op m en t stat us for T B trea tm en t 3 Ref erenc es Fou rth g en er ati on MFX (A ve lox ®) Ap pr ov ed 400 Ac ute ba cteri al s inu si tis , a cute b ac teri al ex ac erbat ion of c hroni c bronc hi tis , c om m un ity ac qu ired p neu m on ia , (un )c om pl ic ate d SS SI, c om pl ic ated ab dom ina l inf ec tion s Pha se III/ IV 6 (20 8;4 08 ;40 9) New g en era tio n SF X (Z ag am ®) Di sc on tinu ed n.a. n.a. Pha se I (40 8;4 10 ) ST X Unk no w n n.a. n.a. None CLX Unk no w n n.a. n.a. None G PX (Rax ar®) Di sc on tinu ed n.a. n.a. None (408 ) G MX (F ac tiv e®) Ap pr ov ed 320 Ac ute ex ac erbat ion or c hro ni c bronc hi tis , c om m un ity - ac qu ire d p ne um on ia None (408 ) TF X (T rov an ®) Di sc on tinu ed n.a. n.a. None (408 ) LM X (Ma xaq ui n® ) Di sc on tinu ed n.a. n.a. G NX (G arenox ac in® ) Ap pr ov ed 400 Mi ld t o m od erate c om m un ity -ac qu ired pn eum on ia, ac ut e m ax illa ry s in us itis None (411 ) DC -1 59 a Unk no wn n.a. n.a. None 1 The m ar keti ng s tat us is ind ic ate d as the s tat e of the F Q on the m ar ket of the Uni te d Sta tes an d or Euro pe an Uni on ; 2 In di cat ed in ad ul ts ( at lea st 18 y ears ) inf ec ted wi th s us cep tib le m ic ro organ is m s un les s in di cate d oth erw is e; 3 Th e c lin ic al de ve lo pm en t s tat us w as ind ic at ed as “no ne ” whe n n o P has e I to IV c lini ca l trai l r eg is tered on c lini ca ltr ial s.go v or av ai lab le as li ter atu re on P ubm ed ; 4 In c hi ldren; 5 In adu lts a nd c hi ldren; 6 Mu lti drug res is tan t tu be rc ul os is ; 7 The m ar keti ng stat us an d/ or the r eg is tere d ind ic at ion w as ind ic ate d as “ un kno w n” w he n reg is te red da ta was no t a va ila bl e on fda .go v or em ea .eu rop e.e u; 8 D is con tinu ati on du e t o c on si de rat io n o f c om m erc ial po te nti al ; FQ = fl uoroqu ino lo ne , T B = tu be rc ul os is , n .a. = not a pp lic ab le, SS SI = s ki n a nd s ki n s truc ture i nf ec tion s.

Methods

A PubMed search of non-editorial, non-review publications in English was performed, using the keywords “fluoroquinolones” (OR specific name(s)) AND “tuberculosis” (OR “multi-drug resistant tuberculosis” OR “extensively drug resistant tuberculosis”) in combination with more subject specified keywords, including “pharmacokinetics”, “plasma”, “cerebrospinal fluid”, “alveolar cell”, “epithelial lining fluid”, “saliva”, “absorption”, “distribution”, “metabolism”, “elimination” and “protein binding” for the pharmacokinetic part; “pharmacodynamics”, “resistance”, “cross resistance”, “critical concentration”, “multi-drug resistance” and “extensively drug resistance” for the microbiological susceptibility and pharmacodynamic part; and “drug interaction” for the drug-drug interaction part. The limitations “human”, “clinical trial”, “randomized controlled trial”, “case reports”, “comperative study”, “controlled clinical trial” and the keyword “NOT in vitro” were added to the drug-drug interaction searches, to include only clinically important interactions proven in human subjects. Publications distillated out of the ‘pharmacodynamic-searches’ (i.e. microbiological susceptibility and pharmacodynamic part) were only included when published in the last ten years, because the clinical importance of older microbiological susceptibility data cannot be guaranteed. All searches were performed with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, moxifloxacin, sparfloxacin, sitafloxacin, clinafloxacin, grepafloxacin, gemifloxacin, trovafloxacin, garenoxacin, lomefloxacin and DC-159a.

Pharmacokinetics

To describe the pharmacokinetic (PK) differences between FQs the following processes

have to be evaluated: absorption, distribution, metabolism and excretion. In Table 2 a

summary of PK properties of the most important FQs in the current TB treatment, including CFX, OFX, LFX, GFX and MFX is shown. In general, FQs have a favourable PK profile. This means that the orally administered FQs are absorbed for a substantial part of the administered dose (>78% (50-54)) and therefore not subjected to substantial first-pass metabolism. Intake with or without food can alter absorption of drugs significantly. Evaluation of the food-drug interactions is therefore important for the practicing physician as it may have

an impact on treatment outcome. In Table 3 an overview is presented on the currently

available data. FQs are not extensively bound to plasma proteins and may therefore pass cell membranes easily, which results in sufficient tissue concentrations to adequately treat infections. As to the distribution of the FQs, one has to keep in mind that M. tuberculosis is an intracellular pathogen that most of the times will be phagocytosed by alveolar

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Chapter

2

a Table 1 (II) . S tate of c lini ca l de vel op m en t i n T B treatm en t a nd ge neral m ark eti ng s tat us . FQ Ma rk eti ng s tat us oth er t ha n T B 1,7 Reg is tered str en gth (m g) Regi st ered i nd ic at ion 2, 7 Cl ini ca l de vel op m en t stat us for T B trea tm en t 3 Ref erenc es Fou rth g en er ati on MFX (A ve lox ®) Ap pr ov ed 400 Ac ute ba cteri al s inu si tis , a cute b ac teri al ex ac erbat ion of c hroni c bronc hi tis , c om m un ity ac qu ired p neu m on ia , (un )c om pl ic ate d SS SI, c om pl ic ated ab dom ina l inf ec tion s Pha se III/ IV 6 (20 8;4 08 ;40 9) New g en era tio n SF X (Z ag am ®) Di sc on tinu ed n.a. n.a. Pha se I (40 8;4 10 ) ST X Unk no w n n.a. n.a. None CLX Unk no w n n.a. n.a. None G PX (Rax ar®) Di sc on tinu ed n.a. n.a. None (408 ) G MX (F ac tiv e®) Ap pr ov ed 320 Ac ute ex ac erbat ion or c hro ni c bronc hi tis , c om m un ity - ac qu ire d p ne um on ia None (408 ) TF X (T rov an ®) Di sc on tinu ed n.a. n.a. None (408 ) LM X (Ma xaq ui n® ) Di sc on tinu ed n.a. n.a. G NX (G arenox ac in® ) Ap pr ov ed 400 Mi ld t o m od erate c om m un ity -ac qu ired pn eum on ia, ac ut e m ax illa ry s in us itis None (411 ) DC -1 59 a Unk no wn n.a. n.a. None 1 The m ar keti ng s tat us is ind ic ate d as the s tat e of the F Q on the m ar ket of the Uni te d Sta tes an d or Euro pe an Uni on ; 2 In di cat ed in ad ul ts ( at lea st 18 y ears ) inf ec ted wi th s us cep tib le m ic ro organ is m s un les s in di cate d oth erw is e; 3 Th e c lin ic al de ve lo pm en t s tat us w as ind ic at ed as “no ne ” whe n n o P has e I to IV c lini ca l trai l r eg is tered on c lini ca ltr ial s.go v or av ai lab le as li ter atu re on P ubm ed ; 4 In c hi ldren; 5 In adu lts a nd c hi ldren; 6 Mu lti drug res is tan t tu be rc ul os is ; 7 The m ar keti ng stat us an d/ or the r eg is tere d ind ic at ion w as ind ic ate d as “ un kno w n” w he n reg is te red da ta was no t a va ila bl e on fda .go v or em ea .eu rop e.e u; 8 D is con tinu ati on du e t o c on si de rat io n o f c om m erc ial po te nti al ; FQ = fl uoroqu ino lo ne , T B = tu be rc ul os is , n .a. = not a pp lic ab le, SS SI = s ki n a nd s ki n s truc ture i nf ec tion s.

Methods

A PubMed search of non-editorial, non-review publications in English was performed, using the keywords “fluoroquinolones” (OR specific name(s)) AND “tuberculosis” (OR “multi-drug resistant tuberculosis” OR “extensively drug resistant tuberculosis”) in combination with more subject specified keywords, including “pharmacokinetics”, “plasma”, “cerebrospinal fluid”, “alveolar cell”, “epithelial lining fluid”, “saliva”, “absorption”, “distribution”, “metabolism”, “elimination” and “protein binding” for the pharmacokinetic part; “pharmacodynamics”, “resistance”, “cross resistance”, “critical concentration”, “multi-drug resistance” and “extensively drug resistance” for the microbiological susceptibility and pharmacodynamic part; and “drug interaction” for the drug-drug interaction part. The limitations “human”, “clinical trial”, “randomized controlled trial”, “case reports”, “comperative study”, “controlled clinical trial” and the keyword “NOT in vitro” were added to the drug-drug interaction searches, to include only clinically important interactions proven in human subjects. Publications distillated out of the ‘pharmacodynamic-searches’ (i.e. microbiological susceptibility and pharmacodynamic part) were only included when published in the last ten years, because the clinical importance of older microbiological susceptibility data cannot be guaranteed. All searches were performed with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, moxifloxacin, sparfloxacin, sitafloxacin, clinafloxacin, grepafloxacin, gemifloxacin, trovafloxacin, garenoxacin, lomefloxacin and DC-159a.

Pharmacokinetics

To describe the pharmacokinetic (PK) differences between FQs the following processes

have to be evaluated: absorption, distribution, metabolism and excretion. In Table 2 a

summary of PK properties of the most important FQs in the current TB treatment, including CFX, OFX, LFX, GFX and MFX is shown. In general, FQs have a favourable PK profile. This means that the orally administered FQs are absorbed for a substantial part of the administered dose (>78% (50-54)) and therefore not subjected to substantial first-pass metabolism. Intake with or without food can alter absorption of drugs significantly. Evaluation of the food-drug interactions is therefore important for the practicing physician as it may have

an impact on treatment outcome. In Table 3 an overview is presented on the currently

available data. FQs are not extensively bound to plasma proteins and may therefore pass cell membranes easily, which results in sufficient tissue concentrations to adequately treat infections. As to the distribution of the FQs, one has to keep in mind that M. tuberculosis is an intracellular pathogen that most of the times will be phagocytosed by alveolar

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macrophages (AM) in the lungs. Mycobacteria that are not incorporated by alveolar macrophages will live and multiply in the lung epithelial lining fluid (ELF). Consequently, the FQ concentration in alveolar cells (AC) or macrophages and ELF may probably best reflect the concentrations of these agents at the site of infection. Those FQs with efficient distribution into cerebrospinal fluid (CSF) will be good candidates in the treatment of tuberculosis meningitis (TBM). The brain distribution of FQs is limited by multiple efflux transporters, including Pgp, MRP-1, and an unknown anion exchange transporter (55). Lastly, penetration of FQs into saliva is worth to evaluate, considering that pharmacokinetic studies and therapeutic drug monitoring (TDM) in saliva may be a simple, non-invasive and attractive alternative in special patient groups, including children, and in resource limited countries. The available data on penetration into AM, ELF, CSF and saliva of FQs is listed in

Table 4. Following their distribution, FQs are predominantly metabolized in the liver and

eliminated renally. Dose adjustment based on hepatic and renal function is only needed in severe cases. FQs can even be advised in case of liver function disturbances caused by first line anti-tuberculosis agents (9). Despite several similar general properties of the FQs there are differences between individual drugs that make one FQ to be preferred over another. Table 2 . Mu lti pl e d os e p harm ac ok ine tic propert ies of fl uo roq ui nol on es (F Q ) i n pl as m a. FQ Dai ly do sag e Sub jec ts O ral bi o-av ail ab ilit y (%) Tmax (h) 1 Cma x (m g/L ) T1/2 (h) AU C (m g* h/ L) Fr ac tion un bo un d Ref erenc es S ec on d g en erat io n CFX 400 500 HV HV 78 (1 ) 2 (1 -2) (4 .3 ) 2 (0 .6 – 2 .5 ) (6 ) 2 (4 -7) (1 2.1 ) 2 (2 .6 – 10. 2) 0.6 0 (50; 59; 412 ) (67; 68; 412 ;4 13 ) OF X 400 600 800 HV HV HV 95 1/2 2 (2 ) (1 ) (2 ) 5. 8 /7. 2 2 (3 .7 ) (8 .0 ) (9 .8 ) 7 2 – 8 3 (5 2 ) (7 ) (7 ) 41. 2 / 29. 0 2 – 43 .5 2 (18. 2/ 19. 8 2 ) (6 0.8 ) (8 5.3 ) 0.7 5 (52; 41 3-415 ) (76 ) (76 ) Thi rd g en er ati on GF X 400 400 HV TB 96 (1 .4 ) 2 (3 .8 ) 3.7 1 (8 .6 ) 5 1 (3 3.5 ) 0.8 0 (53; 10 5; 26 5) (252 ) LFX 500 750 1000 1000 HV HV HV TB 99 (1 ) 3 2 ₁ 5.7 (5 .2 – 6 .1 ) 12. 4 2 (11. 3 2 ) 9.2 2 11. 6 1 8 (6 -7) 8 2 2 ₇ 1 ₇ 47 .5 (4 6.1 – 4 7. 7) 103 2 (90. 9 2 ) 103. 6 2 0. 60 -0. 70 (54; 67; 93 ) (92 ) (90 ) (252 ) Fou rth g en er ati on MF X 400 400 600 800 800 HV TB HV HV TB 86 – 92 2 (1 2 – 2) 1 2 (1 – 3) 3 2 3.2 (2 .5 – 3 .6 2) 2.5 1 – 5 .9 1 5.7 (3 .2 – 4 .2 ) 4.7 3.7 1 15 ( 9 – 16) 3 7 1 – 8 1 14 ( 9 – 13) 12 1 6 33. 9 – 41. 9 ( 26 .9 – 34. 6) 3 24. 8 1 60 .3 (3 9.9 – 5 0. 3) 59. 9 38. 3 1 0.6 0.6– 0. 9 (51; 11 4; 11 5; 11 7; 34 3) (118; 252 ) (114; 115 ) (115 ) (123 ) Data are pres ente d as ran ge of pu bl is hed (ge om etri c) m ea n un les s i nd ic ated ot he rw is e wi th si ng le do se ph ar m ac ok ine tic s be tween br ac kets , 1 da ta pres en ted as m ed ian ; 2 intra ven ou s i ns tea d of oral do sa ge ; 3 in trav eno us an d oral d os ag e; HV = h ea lth y vo lun tee rs , TB = tub erc ul os is pa tie nts , Cmax = m ax imu m con cen trat ion , Tmax = ti m e c orr es po nd ing to Cma x , A UC = are a u nde r t he c on ce ntra tion -ti m e c urv e, FQ = fl uo ro qu in ol one .

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Chapter

2

a

macrophages (AM) in the lungs. Mycobacteria that are not incorporated by alveolar macrophages will live and multiply in the lung epithelial lining fluid (ELF). Consequently, the FQ concentration in alveolar cells (AC) or macrophages and ELF may probably best reflect the concentrations of these agents at the site of infection. Those FQs with efficient distribution into cerebrospinal fluid (CSF) will be good candidates in the treatment of tuberculosis meningitis (TBM). The brain distribution of FQs is limited by multiple efflux transporters, including Pgp, MRP-1, and an unknown anion exchange transporter (55). Lastly, penetration of FQs into saliva is worth to evaluate, considering that pharmacokinetic studies and therapeutic drug monitoring (TDM) in saliva may be a simple, non-invasive and attractive alternative in special patient groups, including children, and in resource limited countries. The available data on penetration into AM, ELF, CSF and saliva of FQs is listed in

Table 4. Following their distribution, FQs are predominantly metabolized in the liver and

eliminated renally. Dose adjustment based on hepatic and renal function is only needed in severe cases. FQs can even be advised in case of liver function disturbances caused by first line anti-tuberculosis agents (9). Despite several similar general properties of the FQs there are differences between individual drugs that make one FQ to be preferred over another. Table 2 . Mu lti pl e d os e p harm ac ok ine tic propert ies of fl uo roq ui nol on es (F Q ) i n pl as m a. FQ Dai ly do sag e Sub jec ts O ral bi o-av ail ab ilit y (%) Tmax (h) 1 Cma x (m g/L ) T1/2 (h) AU C (m g* h/ L) Fr ac tion un bo un d Ref erenc es S ec on d g en erat io n CFX 400 500 HV HV 78 (1 ) 2 (1 -2) (4 .3 ) 2 (0 .6 – 2 .5 ) (6 ) 2 (4 -7) (1 2.1 ) 2 (2 .6 – 10. 2) 0.6 0 (50; 59; 412 ) (67; 68; 412 ;4 13 ) OF X 400 600 800 HV HV HV 95 1/2 2 (2 ) (1 ) (2 ) 5. 8 /7. 2 2 (3 .7 ) (8 .0 ) (9 .8 ) 7 2 – 8 3 (5 2 ) (7 ) (7 ) 41. 2 / 29. 0 2 – 43 .5 2 (18. 2/ 19. 8 2 ) (6 0.8 ) (8 5.3 ) 0.7 5 (52; 41 3-415 ) (76 ) (76 ) Thi rd g en er ati on GF X 400 400 HV TB 96 (1 .4 ) 2 (3 .8 ) 3.7 1 (8 .6 ) 5 1 (3 3.5 ) 0.8 0 (53; 10 5; 26 5) (252 ) LFX 500 750 1000 1000 HV HV HV TB 99 (1 ) 3 2 ₁ 5.7 (5 .2 – 6 .1 ) 12. 4 2 (11. 3 2) 9.2 2 11. 6 1 8 (6 -7) 8 2 2 ₇ 1 ₇ 47 .5 (4 6.1 – 4 7. 7) 103 2 (90. 9 2) 103. 6 2 0. 60 -0. 70 (54; 67; 93 ) (92 ) (90 ) (252 ) Fou rth g en er ati on MF X 400 400 600 800 800 HV TB HV HV TB 86 – 92 2 (1 2 – 2) 1 2 (1 – 3) 3 2 3.2 (2 .5 – 3 .6 2 ) 2.5 1 – 5 .9 1 5.7 (3 .2 – 4 .2 ) 4.7 3.7 1 15 ( 9 – 16) 3 7 1 – 8 1 14 ( 9 – 13) 12 1 6 33. 9 – 41. 9 ( 26 .9 – 34. 6) 3 24. 8 1 60 .3 (3 9.9 – 5 0. 3) 59. 9 38. 3 1 0.6 0.6– 0. 9 (51; 11 4; 11 5; 11 7; 34 3) (118; 252 ) (114; 115 ) (115 ) (123 ) Data are pres ente d as ran ge of pu bl is hed (ge om etri c) m ea n un les s i nd ic ated ot he rw is e wi th si ng le do se ph ar m ac ok ine tic s be tween br ac kets , 1 da ta pres en ted as m ed ian ; 2 intra ven ou s i ns tea d of oral do sa ge ; 3 in trav eno us an d oral d os ag e; HV = h ea lth y vo lun tee rs , TB = tub erc ul os is pa tie nts , Cmax = m ax imu m con cen trat ion , Tmax = ti m e c orr es po nd ing to Cma x , A UC = are a u nde r t he c on ce ntra tion -ti m e c urv e, FQ = fl uo ro qu in ol one .

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Table 3 (I) . Inf lue nc e o f f oo d o n f lu oroq ui nol on e ph arm ac ok ine tic s. FQ Dai ly d os ag e (m g) Fo od S ubj ec t No. S tu dy ty pe Res ul t o f c o a dm in is tra tio n C lini cal rel ev an ce Ref ere Cma x AUC ot her S ec on d g en erat io n CFX 500 (sus pen si on) sta ndar di ze d lunc h HV 68 R an dom iz ed, cr oss o ve r -11% 2, 3,5 +1 3% 2, 3, 5 Co ad m in is tra tio n i s pos si bl e (256 500 ent er al fe edi ng P 26 R an dom iz ed, cr oss o ve r -43% (v s. or al ); -37% ( v s. g -tu be) ; -59% (v s. j-tu be ) 3 ,5 -27% (v s. or al ); -53% (v s. g -tu be ); -67% (v s. j-tu be ) 3 ,5 Tma x 1,3: +2 00 % (o ra l); -50% (g -tu be ); +1 00% 2 (j -tube) A n on q ui nol one a gent is pre fe rre d (57 750 ent er al fe edi ng (En su re ) HV 13 R an dom iz ed, 4-wa y cr oss o ve r -48% 3 -28% 3 Tma x 3 : +1 63 % S w itc hi ng from par en te ra l to o ra l CFX in p at ie nt s rec ei vi ng E ns ur e c oul d res ul t i n u nd es irabl y l ow C FX c onc ent rat ions (56 500 or ange ju ic e (12 o unc es ) HV 15 R an dom iz ed, open -la bel , 3 -w ay c ros s o ver -23% -22% CFX s ho ul d be ta ke n o n an e m pt y s tom ac h w ith wa te r (257 500 ca lci um fo rti fie d o ra ng e ju ic e HV 15 R an dom iz ed, open -la bel , 3 -w ay c ros s o ver -41% -38% C FX s houl d be ta ke n o n an e m pt y s tom ac h w ith wa te r (257 P har m ac ok in et ic d at a i s p re se nt ed a s ( geo m et ric ) m ean in pl as m a u nl es s i ndi cat ed o ther w is e; 1 D at a p re sen te d a s m ed ian ; 2 N o s ta tis tic ally s ig ni fic ant e ffec t ( p> 0. 05) ; 3 Se ru m ins tead of p las m a; 4N as oga st ric tub e a nd e nt er al fee di ng n ot s ta ndar di ze d; 5Leas t s quar e; F Q = fl uor oqui nol one, H V = h ea lth y v ol unt eer s, P = p at ient s, Cma x = c onc ent ra tio n cor re spon di ng to tim e to rea ch m ax im um (i .e . Tma x ), AU C = a rea u nder the c on cent rat io n-tim e c urv e, C l/F = to ta l o ra l c le ar an ce , Vz /F = appar ent v ol um e o f di st rib ut io n d ur ing th e te rm inal pha se, j-tu be = jej uno st om y t ube, g -tu be = gas tro st om y tube. Table 3 (II) . Inf lue nc e o f f oo d o n f luo ro qu ino lon e p ha rm ac ok in eti cs . FQ Dai ly d os ag e (m g) Fo od S ubj ec t No. S tu dy ty pe Res ul t o f c o a dm in is tra tio n C lini cal rel ev an ce Ref ere Cma x AUC ot her S ec on d g en erat io n CFX 500 300 m l w at er , m ilk o r y og hur t HV 7 R an dom iz ed, 3-w ay c ros s ov er -36% ( m ilk ) -47%( yogh ur t) -30% ( m ilk ) -36% ( yogh ur t) In ge st io n o f l ar ge a m oun t of di ar y p rodu ct s i n liq ui d fo rm w ith CFX is n ot re com m en ded (58 OF X 400 ent er al fe edi ng (En su re ) HV 13 R an dom iz ed, 4-wa y cr oss o ve r -36% 3 -10% 3 Tma x +1 52% 3 E ns ur e h as a c lini cal ly ins igni fic ant ef fe ct o n O FX a bs orp tio n, O FX a bs or pt io n w ill b e si gn ifi ca nt ly le ss a ffe ct ed by En su re th an CFX (56 200 st an dar di ze d br eak fa st HV 6 4-wa y cr oss o ve r No e ffe ct 2 -5% 2 No eff ec t o f f oo d o n OFX phar m ac ok inet ic s (258 Thi rd g en er ati on GF X 400 (crus hed ta bl et sus pen si on) en te ra l fe edi ng 4 P 16 R an dom iz ed, 2-wa y cr oss o ve r Unk no w n -2% to + 9% 2,3 M or e r es ear ch in cr iti cal il l pat ie nt s i s nee ded to conf irm the co a dm ini st ra tion of c ru she d G FX a nd fo od v ia a n as oga st ric tu be (259 P har m ac ok in et ic d at a i s p re se nt ed a s ( geo m et ric ) m ean in pl as m a u nl es s i ndi cat ed o ther w is e; 1 Dat a p re sen te d a s m ed ian ; 2 No s ta tis tic al ly s ig ni fic an t e ffe ct (p >0 .0 5); 3 Se ru m ins tead of p las m a; 4N as oga st ric tub e a nd e nt er al fee di ng n ot s ta ndar di ze d; 5Leas t s quar e; F Q = fl uor oqui nol one, H V = h ea lth y v ol unt eer s, P = p at ient s, Cma x = c onc ent ra tio n cor re spon di ng to tim e to rea ch m ax im um (i .e . Tma x ), A U C = ar ea u nder the c on cent rat io n-tim e c urv e, C l/F = to ta l o ra l c le ar an ce , Vz /F = appar ent v ol um e of di st rib ut io n dur ing t he te rm inal pha se, j-tu be = jej uno st om y t ube, g -tu be = gas tro st om y tube.

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Chapter

2

a Table 3 (I) . Inf lue nc e o f f oo d o n f lu oroq ui nol on e ph arm ac ok ine tic s. FQ Dai ly d os ag e (m g) Fo od S ubj ec t No. S tu dy ty pe Res ul t o f c o a dm in is tra tio n C lini cal rel ev an ce Ref ere Cma x AUC ot her S ec on d g en erat io n CFX 500 (sus pen si on) sta ndar di ze d lunc h HV 68 R an dom iz ed, cr oss o ve r -11% 2, 3,5 +1 3% 2, 3, 5 Co ad m in is tra tio n i s pos si bl e (256 500 ent er al fe edi ng P 26 R an dom iz ed, cr oss o ve r -43% (v s. or al ); -37% ( v s. g -tu be) ; -59% (v s. j-tu be ) 3 ,5 -27% (v s. or al ); -53% (v s. g -tu be ); -67% (v s. j-tu be ) 3 ,5 Tma x 1,3 : +2 00 % (o ra l); -50% (g -tu be ); +1 00% 2 (j -tube) A n on q ui nol one a gent is pre fe rre d (57 750 ent er al fe edi ng (En su re ) HV 13 R an dom iz ed, 4-wa y cr oss o ve r -48% 3 -28% 3 Tma x 3 : +1 63 % S w itc hi ng from par en te ra l to o ra l CFX in p at ie nt s rec ei vi ng E ns ur e c oul d res ul t i n u nd es irabl y l ow C FX c onc ent rat ions (56 500 or ange ju ic e (12 o unc es ) HV 15 R an dom iz ed, open -la bel , 3 -w ay c ros s o ver -23% -22% CFX s ho ul d be ta ke n o n an e m pt y s tom ac h w ith wa te r (257 500 ca lci um fo rti fie d o ra ng e ju ic e HV 15 R an dom iz ed, open -la bel , 3 -w ay c ros s o ver -41% -38% C FX s houl d be ta ke n o n an e m pt y s tom ac h w ith wa te r (257 P har m ac ok in et ic d at a i s p re se nt ed a s ( geo m et ric ) m ean in pl as m a u nl es s i ndi cat ed o ther w is e; 1 D at a p re sen te d a s m ed ian ; 2 N o s ta tis tic ally s ig ni fic ant e ffec t ( p> 0. 05) ; 3 Se ru m ins tead of p las m a; 4 N as oga st ric tub e a nd e nt er al fee di ng n ot s ta ndar di ze d; 5 Leas t s quar e; F Q = fl uor oqui nol one, H V = h ea lth y v ol unt eer s, P = p at ient s, Cma x = c onc ent ra tio n cor re spon di ng to tim e to rea ch m ax im um (i .e . Tma x ), AU C = a rea u nder the c on cent rat io n-tim e c urv e, C l/F = to ta l o ra l c le ar an ce , Vz /F = appar ent v ol um e o f di st rib ut io n d ur ing th e te rm inal pha se, j-tu be = jej uno st om y t ube, g -tu be = gas tro st om y tube. Table 3 (II) . Inf lue nc e o f f oo d o n f luo ro qu ino lon e p ha rm ac ok in eti cs . FQ Dai ly d os ag e (m g) Fo od S ubj ec t No. S tu dy ty pe Res ul t o f c o a dm in is tra tio n C lini cal rel ev an ce Ref ere Cma x AUC ot her S ec on d g en erat io n CFX 500 300 m l w at er , m ilk o r y og hur t HV 7 R an dom iz ed, 3-w ay c ros s ov er -36% ( m ilk ) -47%( yogh ur t) -30% ( m ilk ) -36% ( yogh ur t) In ge st io n o f l ar ge a m oun t of di ar y p rodu ct s i n liq ui d fo rm w ith CFX is n ot re com m en ded (58 OF X 400 ent er al fe edi ng (En su re ) HV 13 R an dom iz ed, 4-wa y cr oss o ve r -36% 3 -10% 3 Tma x +1 52% 3 E ns ur e h as a c lini cal ly ins igni fic ant ef fe ct o n O FX a bs orp tio n, O FX a bs or pt io n w ill b e si gn ifi ca nt ly le ss a ffe ct ed by En su re th an CFX (56 200 st an dar di ze d br eak fa st HV 6 4-wa y cr oss o ve r No e ffe ct 2 -5% 2 No eff ec t o f f oo d o n OFX phar m ac ok inet ic s (258 Thi rd g en er ati on GF X 400 (crus hed ta bl et sus pen si on) en te ra l fe edi ng 4 P 16 R an dom iz ed, 2-wa y cr oss o ve r Unk no w n -2% to + 9% 2,3 M or e r es ear ch in cr iti cal il l pat ie nt s i s nee ded to conf irm the co a dm ini st ra tion of c ru she d G FX a nd fo od v ia a n as oga st ric tu be (259 P har m ac ok in et ic d at a i s p re se nt ed a s ( geo m et ric ) m ean in pl as m a u nl es s i ndi cat ed o ther w is e; 1 Dat a p re sen te d a s m ed ian ; 2 No s ta tis tic al ly s ig ni fic an t e ffe ct (p >0 .0 5); 3 Se ru m ins tead of p las m a; 4N as oga st ric tub e a nd e nt er al fee di ng n ot s ta ndar di ze d; 5Leas t s quar e; F Q = fl uor oqui nol one, H V = h ea lth y v ol unt eer s, P = p at ient s, Cma x = c onc ent ra tio n cor re spon di ng to tim e to rea ch m ax im um (i .e . Tma x ), A U C = ar ea u nder the c on cent rat io n-tim e c urv e, C l/F = to ta l o ra l c le ar an ce , Vz /F = appar ent v ol um e of di st rib ut io n dur ing t he te rm inal pha se, j-tu be = jej uno st om y t ube, g -tu be = gas tro st om y tube.

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Table 3 (III) . Inf lue nc e o f f oo d o n f luo ro qu ino lon e p ha rm ac ok ine tic s. Dai ly d os ag e (m g) Fo od S ubj ec t No. S tu dy ty pe Res ul t o f c o a dm in is tra tio n C lini cal rel ev an ce Re fe re Cma x AUC ot her g en er ati on 400 ca lci um fo rti fie d or ange ju ic e HV 16 R an dom iz ed, open -la bel , 3 -w ay c ros s o ver -15% 2 -12% Clt /F + 15%; Vz /F + 13% Ad m in is tra tio n o f GFX w ith non -fo rti fied food or o n an em pt y s to m ac h. (260 200 light m or ni ng m eal HV 6 -4% 2,3 -12% 3 The e ffec t o f f ood w as negl igi bl e (105 500 S ta ndar di zed high -fa t br eak fa st HV 24 R an dom iz ed, open -la bel , 3 -w ay c ros s o ver -14% 2 -10% Tma x + 100% 1 LF X c oul d be a dm ini st er ed wi th food (91 500 jui ce a nd cer ea l HV 16 R an dom iz ed, open -la bel , 3 -w ay c ros s o ver -23% -15% Tmax +5 7% ; Cl/ F +1 7% Vz /F + 24% E ffec t of c er ea l a nd jui ce (lac k of bi o equ iv al en ce bas ed o n C ma x ) (261 500 jui ce, c er ea l and m ilk HV 16 R an dom iz ed, open l abe l, 3-w ay c ros s o ver -24% -16% Tma x + 46% C l/F + 21% Vz /F + 21 % E ffec t of c er ea l, jui ce and m ilk (L ac k o f b io equi va len ce bas ed o n C ma x ) (261 P har m ac ok in et ic d at a i s p re se nt ed a s ( geo m et ric ) m ean in pl as m a u nl es s i ndi cat ed o ther w is e; 1D at a pr es en ted as m ed ian ; 2No s ta tis tic al ly s ig ni fic an t e ffe ct (p >0 .0 5); 3Se ru m ins tead of p las m a; 4 N as oga st ric tub e a nd e nt er al fee di ng n ot s ta ndar di ze d; 5 Leas t s quar e; F Q = fl uor oqui nol one, H V = h ea lth y v ol unt eer s, P = p at ient s, Cma x = c onc ent ra tio n cor re spon di ng to tim e to re ac h m ax im um (i .e . Tma x ), A U C = ar ea u nder the c on cent rat io n-tim e c urv e, C l/F = to ta l o ra l c le ar an ce , Vz /F = appar ent v ol um e o f di st rib ut io n d ur ing th e te rm inal pha se, j-tu be = jej uno st om y t ube, g -tu be = gas tro st om y tube. Table 3 (I V) . Inf lu en ce of fo od o n f luo ro qu ino lon e p ha rm ac ok ine tic s. Dai ly d os ag e (m g) Fo od S ubj ec t No. S tu dy ty pe Res ul t o f c o a dm in is tra tio n C lini cal rel ev an ce Ref ere Cma x AUC ot her g en er ati on 500 ca lci um fo rti fie d o ra ng e ju ic e HV 16 R an dom iz ed, open -la bel , 3 -w ay c ros s o ver -18% -8% 2 Tma x +5 8% LF X s houl d b e ta ken o n an e m pt y s tom ac h w ith wa te r (262 ) rth g en er ati on 400 ent er al fe edi ng HV 12 R an dom iz ed, open -la bel , 3 - wa y cr oss o ve r -12% 3 -9% 2,3 No e ffe ct o n Tma x 1,2 ,3 C ru shed M FX c oul d be adm ini st er ed w ith foo d vi a a n as og as tri c t ube (113 ) 400 Yoghur t (250 m g) HV 12 R an dom iz ed, open -la bel , 2 -w ay c ros s o ver -15% 5 -6% 5 Tma x + 213% 1 Con co m ita nt tre at m en t o f dai ry p rod uc ts is p os si bl e w ith out s pec ial rec om m enda tio ns (293 ) P har m ac ok in et ic d at a i s p re se nt ed a s ( geo m et ric ) m ean in pl as m a u nl es s i ndi cat ed o ther w is e; 1 D at a p re sen te d a s m ed ian ; 2 No s ta tis tic al ly s igni fic ant e ffec t ( p> 0. 05) ; 3 Se ru m ins tead of p las m a; 4Nas oga st ric tub e a nd e nt er al fee di ng n ot s ta ndar di ze d; 5Leas t s quar e; F Q = fl uor oqui nol one, H V = h ea lth y v ol unt eer s, P = p at ient s, Cma x = c onc ent ra tio n cor re spon di ng to tim e to rea ch m ax im um (i .e . Tma x ), A U C = ar ea u nder the c on cent rat io n-tim e c urv e, C l/F = to ta l o ra l c le ar an ce , Vz /F = appar ent v ol um e o f di st rib ut io n d ur ing th e te rm inal pha se, j-tu be = jej uno st om y t ube, g -tu be = gas tro st om y tube.

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Chapter

2

a Table 3 (III) . Inf lue nc e o f f oo d o n f luo ro qu ino lon e p ha rm ac ok ine tic s. Dai ly d os ag e (m g) Fo od S ubj ec t No. S tu dy ty pe Res ul t o f c o a dm in is tra tio n C lini cal rel ev an ce Re fe re Cma x AUC ot her g en er ati on 400 ca lci um fo rti fie d or ange ju ic e HV 16 R an dom iz ed, open -la bel , 3 -w ay c ros s o ver -15% 2 -12% Clt /F + 15%; Vz /F + 13% Ad m in is tra tio n o f GFX w ith non -fo rti fied food or o n an em pt y s to m ac h. (260 200 light m or ni ng m eal HV 6 -4% 2,3 -12% 3 The e ffec t o f f ood w as negl igi bl e (105 500 S ta ndar di zed high -fa t br eak fa st HV 24 R an dom iz ed, open -la bel , 3 -w ay c ros s o ver -14% 2 -10% Tma x + 100% 1 LF X c oul d be a dm ini st er ed wi th food (91 500 jui ce a nd cer ea l HV 16 R an dom iz ed, open -la bel , 3 -w ay c ros s o ver -23% -15% Tmax +5 7% ; Cl/ F +1 7% Vz /F + 24% E ffec t of c er ea l a nd jui ce (lac k of bi o equ iv al en ce bas ed o n C ma x ) (261 500 jui ce, c er ea l and m ilk HV 16 R an dom iz ed, open l abe l, 3-w ay c ros s o ver -24% -16% Tma x + 46% C l/F + 21% Vz /F + 21 % E ffec t of c er ea l, jui ce and m ilk (L ac k o f b io equi va len ce bas ed o n C ma x ) (261 P har m ac ok in et ic d at a i s p re se nt ed a s ( geo m et ric ) m ean in pl as m a u nl es s i ndi cat ed o ther w is e; 1D at a pr es en ted as m ed ian ; 2No s ta tis tic al ly s ig ni fic an t e ffe ct (p >0 .0 5); 3Se ru m ins tead of p las m a; 4 N as oga st ric tub e a nd e nt er al fee di ng n ot s ta ndar di ze d; 5 Leas t s quar e; F Q = fl uor oqui nol one, H V = h ea lth y v ol unt eer s, P = p at ient s, Cma x = c onc ent ra tio n cor re spon di ng to tim e to re ac h m ax im um (i .e . Tma x ), A U C = ar ea u nder the c on cent rat io n-tim e c urv e, C l/F = to ta l o ra l c le ar an ce , Vz /F = appar ent v ol um e o f di st rib ut io n d ur ing th e te rm inal pha se, j-tu be = jej uno st om y t ube, g -tu be = gas tro st om y tube. Table 3 (I V) . Inf lu en ce of fo od o n f luo ro qu ino lon e p ha rm ac ok ine tic s. Dai ly d os ag e (m g) Fo od S ubj ec t No. S tu dy ty pe Res ul t o f c o a dm in is tra tio n C lini cal rel ev an ce Ref ere Cma x AUC ot her g en er ati on 500 ca lci um fo rti fie d o ra ng e ju ic e HV 16 R an dom iz ed, open -la bel , 3 -w ay c ros s o ver -18% -8% 2 Tma x +5 8% LF X s houl d b e ta ken o n an e m pt y s tom ac h w ith wa te r (262 ) rth g en er ati on 400 ent er al fe edi ng HV 12 R an dom iz ed, open -la bel , 3 - wa y cr oss o ve r -12% 3 -9% 2,3 No e ffe ct o n Tma x 1,2 ,3 C ru shed M FX c oul d be adm ini st er ed w ith foo d vi a a n as og as tri c t ube (113 ) 400 Yoghur t (250 m g) HV 12 R an dom iz ed, open -la bel , 2 -w ay c ros s o ver -15% 5 -6% 5 Tma x + 213% 1 Con co m ita nt tre at m en t o f dai ry p rod uc ts is p os si bl e w ith out s pec ial rec om m enda tio ns (293 ) P har m ac ok in et ic d at a i s p re se nt ed a s ( geo m et ric ) m ean in pl as m a u nl es s i ndi cat ed o ther w is e; 1 D at a p re sen te d a s m ed ian ; 2 No s ta tis tic al ly s igni fic ant e ffec t ( p> 0. 05) ; 3 Se ru m ins tead of p las m a; 4Nas oga st ric tub e a nd e nt er al fee di ng n ot s ta ndar di ze d; 5Leas t s quar e; F Q = fl uor oqui nol one, H V = h ea lth y v ol unt eer s, P = p at ient s, Cma x = c onc ent ra tio n cor re spon di ng to tim e to rea ch m ax im um (i .e . Tma x ), A U C = ar ea u nder the c on cent rat io n-tim e c urv e, C l/F = to ta l o ra l c le ar an ce , Vz /F = appar ent v ol um e o f di st rib ut io n d ur ing th e te rm inal pha se, j-tu be = jej uno st om y t ube, g -tu be = gas tro st om y tube.

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Table 4 . F lu oroqu in ol one ti ss ue pe netrat ion at se vera l ad m ini stered do sa ge s. Dai ly do sag e Su bj ec t tis sue Cma x (m g/L ) tis sue Ti ssu e – to – pl as m a rati o Ref erenc es ec on d g en erat io n 500 HV S aliv a (0 .3 – 1 .0 ) (0 .5 1 – 0. 58) (412; 413; 416 ) X 400 600 800 300 HV HV HV TB S aliv a S aliv a S aliv a P leur al fl ui d 2.1 (1 .7 ) (4 .1 ) (4 .2 ) 0.4 (0 .4 3) (0 .4 0 – 0. 57) (0 .4 0 – 0. 56) (413; 417 ) (76 ) (76 ) (79 ) rd g en er ati on X 200 HV EL F 1.4 (107 ) 500 ₁₀₀₀ 500 ₁₀₀₀ HV HV HV HV AM AM ELF ELF 28. 5 51. 8 15. 2 25. 8 5.8 5.5 3.0 2.9 (94 ) (90 ) (94 ) (90 ) rth g en er ati on X 50 – 20 0 400 400 800 400 400 HV HV TB TB 2_HV 2_HV S aliv a S aliv a CSF CSF AM ELF (0 .3 – 1 .6 ) (3 .6 ) 1.3 1 2.2 1 123. 3 11. 7 (0 .5 0 – 1.0 ) (1 .0 ) 0.8 2 0.7 1 32 5.2 (115 ) (124 ) (123 ) (123 ) (94 ) (94 ) Data are pres en ted as ran ge of pu bl is he d ( ge om etri c) m ea n un les s ind ic ate d ot he rw is e wi th s ing le do se p ha rm ac ok ine tic s be twee n brac kets ; 1 Data pres en te d as m ed ian ; 2 O ld er adu lts ( m ea n ag e: 62 y ears ) u nd er go in g di agn os tic bro nc ho sc op y; HV = h ea lth y vo lu nte ers , T B = tub erc ul os is pa tien ts , C max = ma xi mu m con cen trat ion , CS F = c ere br os pi na l f lu id, AM = al veo la r m ac rop ha ge s, F Q = fl uor oq ui nol one .

Pharmacokinetic characteristics of the currently used fluoroquinolones

Ciprofloxacin

CFX has a good oral bioavailability of 78% (50) and Cmax is achieved prompt after oral intake.

The AUC and Cmax of CFX are reduced by intake with food (56;57). Even dairy products need

to be avoided (58).

In healthy volunteers, the mean serum protein binding of CFX is 40% and is found irrespective of the absolute concentration studied (i.e. range: 0.5 to 5 mg/L) (59). In contrast, the mouse plasma protein binding seems to depend of the concentration of CFX, i.e. 0 - 67% of the absolute concentration of CFX (range: 0.01 to 50 mg/L) is bound to plasma protein (60). CFX has a high volume of distribution, equal to 3.3 L/kg, at steady state for CFX (61), but it penetrates poorly into ELF and CSF (62-64). ELF concentrations of CFX are higher after multiple oral doses of 500 mg in healthy volunteers and may therefore be dose-dependent (62). Although CFX concentrations found in ELF were lower than in plasma, the concentrations in AM were higher (62). Intrapulmonary administration of CFX seems a good alternative to obtain efficient concentrations of CFX into lung ELF (65) but is not a common route of administration. Constant mean CFX concentration ratios (i.e. 0.5 – 0.7) between saliva and serum are observed, not affected by the amount of dosage (250 – 750 mg) or multiple administration (66) and are equal to the protein unbound CFX fraction (59).

Like other FQs, CFX will mainly be excreted via the renal pathway, reflected in a mean total urine recovery of 37 – 41%, and to a lesser extent in faeces (61;67-69). Low concentrations of four metabolites are detected (69). In case of a creatinine clearance below 60 ml/min, dose adjustments have to be made based on renal function; in case of continuous renal replacement therapy or hemodiafiltration, a daily dosage of 400 mg should be maintained (70;71). Patients with hepatic impairment can be treated with a normal dosage (69;72;73). Finally, CFX pharmacokinetics is not gender- but age-dependent. The observed increase in plasma concentrations in elderly subjects is probably due to a decline in renal function, but probably is not clinically relevant (i.e. 20-30%) (74).

Ofloxacin

The absorption of an oral dosage of OFX is fast and nearly complete (95%) (52).

Co-administration of food with OFX results in reduced exposure and Cmax. Tmax is also prolonged

in comparison with simultaneous administration of OFX and water (56). OFX plasma and serum pharmacokinetics are proportionally increased when escalating the dosage from 600 to 800 mg once daily (75;76).

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Chapter

2

a Table 4 . F lu oroqu in ol one ti ss ue pe netrat ion at se vera l ad m ini stered do sa ge s. Dai ly do sag e Su bj ec t tis sue Cma x (m g/L ) tis sue Ti ssu e – to – pl as m a rati o Ref erenc es ec on d g en erat io n 500 HV S aliv a (0 .3 – 1 .0 ) (0 .5 1 – 0. 58) (412; 413; 416 ) X 400 600 800 300 HV HV HV TB S aliv a S aliv a S aliv a P leur al fl ui d 2.1 (1 .7 ) (4 .1 ) (4 .2 ) 0.4 (0 .4 3) (0 .4 0 – 0. 57) (0 .4 0 – 0. 56) (413; 417 ) (76 ) (76 ) (79 ) rd g en er ati on X 200 HV EL F 1.4 (107 ) 500 ₁₀₀₀ 500 ₁₀₀₀ HV HV HV HV AM AM ELF ELF 28. 5 51. 8 15. 2 25. 8 5.8 5.5 3.0 2.9 (94 ) (90 ) (94 ) (90 ) rth g en er ati on X 50 – 20 0 400 400 800 400 400 HV HV TB TB 2_HV 2_HV S aliv a S aliv a CSF CSF AM ELF (0 .3 – 1 .6 ) (3 .6 ) 1.3 1 2.2 1 123. 3 11. 7 (0 .5 0 – 1.0 ) (1 .0 ) 0.8 2 0.7 1 32 5.2 (115 ) (124 ) (123 ) (123 ) (94 ) (94 ) Data are pres en ted as ran ge of pu bl is he d ( ge om etri c) m ea n un les s ind ic ate d ot he rw is e wi th s ing le do se p ha rm ac ok ine tic s be twee n brac kets ; 1 Data pres en te d as m ed ian ; 2 O ld er adu lts ( m ea n ag e: 62 y ears ) u nd er go in g di agn os tic bro nc ho sc op y; HV = h ea lth y vo lu nte ers , T B = tub erc ul os is pa tien ts , C max = ma xi mu m con cen trat ion , CS F = c ere br os pi na l f lu id, AM = al veo la r m ac rop ha ge s, F Q = fl uor oq ui nol one .

Pharmacokinetic characteristics of the currently used fluoroquinolones

Ciprofloxacin

CFX has a good oral bioavailability of 78% (50) and Cmax is achieved prompt after oral intake.

The AUC and Cmax of CFX are reduced by intake with food (56;57). Even dairy products need

to be avoided (58).

In healthy volunteers, the mean serum protein binding of CFX is 40% and is found irrespective of the absolute concentration studied (i.e. range: 0.5 to 5 mg/L) (59). In contrast, the mouse plasma protein binding seems to depend of the concentration of CFX, i.e. 0 - 67% of the absolute concentration of CFX (range: 0.01 to 50 mg/L) is bound to plasma protein (60). CFX has a high volume of distribution, equal to 3.3 L/kg, at steady state for CFX (61), but it penetrates poorly into ELF and CSF (62-64). ELF concentrations of CFX are higher after multiple oral doses of 500 mg in healthy volunteers and may therefore be dose-dependent (62). Although CFX concentrations found in ELF were lower than in plasma, the concentrations in AM were higher (62). Intrapulmonary administration of CFX seems a good alternative to obtain efficient concentrations of CFX into lung ELF (65) but is not a common route of administration. Constant mean CFX concentration ratios (i.e. 0.5 – 0.7) between saliva and serum are observed, not affected by the amount of dosage (250 – 750 mg) or multiple administration (66) and are equal to the protein unbound CFX fraction (59).

Like other FQs, CFX will mainly be excreted via the renal pathway, reflected in a mean total urine recovery of 37 – 41%, and to a lesser extent in faeces (61;67-69). Low concentrations of four metabolites are detected (69). In case of a creatinine clearance below 60 ml/min, dose adjustments have to be made based on renal function; in case of continuous renal replacement therapy or hemodiafiltration, a daily dosage of 400 mg should be maintained (70;71). Patients with hepatic impairment can be treated with a normal dosage (69;72;73). Finally, CFX pharmacokinetics is not gender- but age-dependent. The observed increase in plasma concentrations in elderly subjects is probably due to a decline in renal function, but probably is not clinically relevant (i.e. 20-30%) (74).

Ofloxacin

The absorption of an oral dosage of OFX is fast and nearly complete (95%) (52).

Co-administration of food with OFX results in reduced exposure and Cmax. Tmax is also prolonged

in comparison with simultaneous administration of OFX and water (56). OFX plasma and serum pharmacokinetics are proportionally increased when escalating the dosage from 600 to 800 mg once daily (75;76).

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A mean concentration-independent protein binding of 25% is found in human sera (52). As for CFX, the mouse plasma protein binding seems to depend of the OFX concentration, i.e. 36 – 100% of the absolute concentration of OFX (range: 0.01 – 50 mg/L) is bound to plasma protein (60). Based on a volume of distribution of 1.2 – 1.4 L/kg observed in healthy volunteers and drug-resistant patients, an effective penetration in extravascular spaces is suggested (52;77). In patients with drug-resistant tuberculosis, OFX penetrates very well into ELF, reflected in an approximately 4 times higher OFX lung concentration in comparison to plasma (78). In addition, OFX penetrates very well in pleural fluid in patients with pleural tuberculosis (79). Although penetration of OFX in both inflamed and non-inflamed meninges is observed after an oral or intravenous dose of 200 mg once-daily, the reached concentrations in CSF do not seem high enough to kill M. tuberculosis effectively (80-83). In the treatment of TB meningitis, efficacy of an intravenous dosage of 400 mg OFX once daily is only suggested in patients with isolates for which the MIC of OFX is 0.125 mg/L (84). Finally, OFX in saliva seems to be suitable for TDM based on the observed OFX concentration ratios (i.e. 0.4 – 0.6) between saliva and plasma which are not dose dependent (76).

Metabolism of OFX is limited and includes three metabolic routes: O-acyl glucuronidation, N-demethylation and N-oxidation (52;85). OFX will particularly (i.e. for at least 73%) be excreted via the renal pathway and the amount of unchanged drug in the urine will be dominant compared to less than 5% of the N-demethyl- and N-oxide metabolites. The route of administration does not influence the amount of metabolites excreted in the urine [52]. Dose adjustment is advised in patients with renal failure (86;87). Since OFX is hardly eliminated by haemodialysis or continuous ambulatory peritoneal dialysis (CAPD), no dose adjustments are necessary in these situations (86-88). Finally, OFX pharmacokinetics are gender-dependent and consequently dose adjustments should be considered in female

patients due to a higher observed AUC0-24h and Cmax in comparison to male patients (89).

Levofloxacin

LFX has a bioavailability of 99% (54) and Cmax is reached within one hour (Table 2).

Proportional increases in Cmax and AUC in plasma were observed when escalating the

dosage from 750 to 1000 mg (90). Although LFX bioavailability is not significantly affected by

intake with a high fat meal, time to reach Cmax will be prolonged by one hour (91).

At steady state (i.e. day 10 (54;92)), the observed volume of distribution is 1.1 - 1.3 L/kg

(61;92). Circa 30 - 40% of LFX is bound to protein (93). For LFX a mean ELF – to – plasma

concentration of 3.0 was reported at an oral dosage of 500 mg in older adults, and a mean

AM – to – plasma concentration ratio of 5.8 was observed (90;94). A long half life in lung

alveolar cells (i.e. t1/2 = 14) was observed in comparison to the half life in plasma and ELF

(i.e. both t1/2 = 8) (90). Adequate TB treatment seems likely, due to AM concentrations

superior to the minimal inhibitory concentration (MIC) of most intracellular pathogens. Despite higher LFX concentrations in plasma after once daily oral administration of 750 mg, no significantly higher LFX concentrations in AM were observed compared to once daily dosing of 500 mg LFX (62). This suggests that in the treatment of a pulmonary infection, a higher dosage will not automatically result in better treatment. However, it must be considered that the pathology of the lungs could have an influence on LFX penetration into lung tissue (95;96). In patients with chronic lung disease, LFX concentrations were not significantly different from those in healthy volunteers. In contrast, penetration of LFX in AM was enhanced in patients with chronic lung disease (95). LFX will also penetrate very well into bone. Consequently, LFX could be a good antimicrobial candidate in the treatment of TB osteomyelitis (97). LFX penetrates in CSF of patients with both inflamed and non inflamed meninges (98;99) and is therefore a potential candidate for the treatment of TBM.

LFX is mainly excreted by the renal pathway. Limited biotransformation is observed for LFX and after 48 hours a mean total urinary recovery of 76-81% is reported (61;67). Therefore dose adjustments have to be made in patients with decreased renal function and in patients receiving haemodialysis or CAPD (92;100). Based on two other studies no dose adjustments have to be made in patients receiving continuous venovenous haemodialysis (CVVH) (101;102). In addition, no dose adjustment seems to be required in patients with hepatic dysfunction (93;103). LFX pharmacokinetics are influenced by gender and age, but not to an extent that the dosage needs to be changed (104).

Gatifloxacin

Gatifloxacin (GFX) absorption is nearly complete (96%) (53) and similar for a single oral or

intravenous dosage (53). Cmax is reached in 1 – 2 hours (105) (Table 2). GFX shows linear

pharmacokinetics in a dosage range of 200 – 800 mg administrated intravenously (106). GFX absorption is not affected by food (105). The half-life of GFX is 7-14 h. Steady state of GFX is reached within 3 days (105;106).

Approximately 20% of GFX is bound to protein (105). Based on a volume of distribution of 1.6 L/kg at steady state (61), good penetration of GFX into extravascular spaces is expected.

In healthy volunteers, the GFX Cmax and AUC found in bronchial ELF was higher than in

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