PK-PD relationships for antiretroviral drugs Richard M.W. Hoetelmans, PharmD, PhD Slotervaart Hospital Dept. of Pharmacy & Pharmacology Amsterdam, The.

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Presentation transcript:

PK-PD relationships for antiretroviral drugs Richard M.W. Hoetelmans, PharmD, PhD Slotervaart Hospital Dept. of Pharmacy & Pharmacology Amsterdam, The Netherlands

PK-PD relationships An attempt to correlate pharmacokinetic parameters of a drug and its efficacy/toxicity. Antiretroviral drugs: focus on the PIs and the NNRTIs.

PK-PD relationships nucleoside analogues reverse transcriptase inhibitors no clear relationships between plasma concentrations and the virological response (might be different for intracellular TP concentrations, but large datasets are lacking). protease inhibitors relationships between the pharmacological exposure and virological response/toxicity have been established (this presentation). non-nucleoside reverse transcriptase inhibitors some indications of relationships between the pharmacological exposure and virological response exist (this presentation).

Indinavir Most studies on PK-PD relationships for antiretroviral drugs have been performed with indinavir in an 800 mg tid dosing regimen with 2 NRTIs.

Indinavir Indinavir and virologic efficacy pretreatmentPK parametersPD parameters Stein et al.NRTIsAUC, Cmin  HIV-1 RNA wk 24 Burger et al.mixedconc. ratio  HIV-1 RNA wk 24 Harris et al.NRTIsCmin1-NAUC (RNA) wk 24 Fletcher et al.NRTIsCmin  HIV-1 RNA wk 24 Murphy et al.NRTIs/naïveAUC, Cmin, Cmax  HIV-1 RNA day 36 Acosta et al.naïveAUC, CminHIV-1 RNA < LOQ

Indinavir Indinavir and virologic efficacy Some (but not all) studies show, in retrospective, relationships between indinavir pharmacokinetics and HIV-1 RNA response. These relationships have mainly been established in NRTI-pretreated patients. Reported pharmacokinetic parameters are AUC, C min, and C max (all correlated). No clear data on such relationships when indinavir is used in combination with (low dose) ritonavir.

Indinavir Indinavir and (renal) toxicity pretreatmentPK parametersPD parameters Dieleman et al.NRTIsconc. ratiourological complaints

Indinavir Indinavir and renal toxicity Anecdotal data show that high exposure to indinavir is associated with an increased risk for urological complaints (flank pain, haematuria, renal colic). It has been hypothesized that C max of indinavir is correlated with renal toxicity. Recent (preliminary) data of the BEST trial suggest that renal toxicity is more often encountered when used in a RTV/IDV 100/800 mg bid regimen as compared to IDV 800 mg tid alone, suggesting that AUC or time > certain concentration rather than C max might be the main determinant of renal toxicity 1. 1 Gatell, XIII IAC, Durban, 2000, abstract WeOrB484

Saquinavir Studies on PK-PD relationships for saquinavir have been performed during monotherapy or when combined with 2 NRTIs

Saquinavir Saquinavir and virologic efficacy pretreatmentPK parametersPD parameters Gieschke et al.naïve (monother)AUC  HIV-1 RNA wk 8 Hoetelmans et al.mixedconc. ratio  HIV-1 RNA wk 48 Hoetelmans et al.naïve (quadruple)conc. ratioinitial HIV-1 RNA decline (wk 2) * Heeswijk et al.naïve (triple)none  HIV-1 RNA wk 48 * Only in a univariate model

Saquinavir Saquinavir and virologic efficacy Some (but not all) studies show, in retrospective, relationships between saquinavir pharmacokinetics and HIV-1 RNA response. These relationships have been established in naïve and NRTI-pretreated patients. Reported pharmacokinetic parameters are AUC and C min (all correlated). No clear data on such relationships when saquinavir is used in combination with (low dose) ritonavir.

Saquinavir Saquinavir and toxicity pretreatmentPK parametersPD parameters Reijers et al.naiveconc. ratiogastrointestinal complaints

Saquinavir Saquinavir and toxicity Higher saquinavir exposure has been linked with increased risk for gastrointestinal complaints. It is unclear which PK parameters is best associated with the occurrence of these side effects.

Nelfinavir Few studies have investigated PK-PD relationships for nelfinavir. The active metabolite (M8) has often not been taken into account.

Nelfinavir Nelfinavir and virologic efficacy pretreatmentPK parametersPD parameters Kerr et al.naïve (triple)2h conc.HIV-1 RNA wk 24 Hoetelmans et al.naïve (quadruple)conc. ratioinitial HIV-1 RNA decline (wk 2)

Nelfinavir and initial decline HIV-1 RNA

Nelfinavir Nelfinavir and virologic efficacy Some studies show, in retrospective, relationships between nelfinavir pharmacokinetics and (initial) HIV-1 RNA response. These relationships have been established in naïve patients.

Nelfinavir Nelfinavir and toxicity pretreatmentPK parametersPD parameters Reijers et al.naiveconc. ratiogastrointestinal complaints

Nelfinavir Nelfinavir and toxicity High nelfinavir exposure has been associated with increased risk for gastrointestinal complaints. It is unclear which PK parameters is best associated with the occurrence of these side effects.

Ritonavir Ritonavir and toxicity pretreatmentPK parametersPD parameters Gatti et al.naiveCmax, Cmingastrointestinal and neurological complaints

Ritonavir Ritonavir and toxicity High ritonavir exposure has been associated with increased risk for gastrointestinal and neurological complaints. These associations have been reported for AUC, C max and C min (all correlated).

Nevirapine Nevirapine and virologic efficacy pretreatmentPK parametersPD parameters Veldkamp et al.naïvemedian conc.  HIV-1 RNA wk 52, initial decline HIV RNA duration of response

Nevirapine Nevirapine and virologic efficacy Limited data on retrospective relationships between nevirapine pharmacokinetics and HIV-1 RNA response (short and long term, durability). These relationships have been established in naïve patients. Reported pharmacokinetic parameter is the median concentration.

NVP PK-PD relationship

Efavirenz Efavirenz and virologic efficacy pretreatmentPK parametersPD parameters Joshi et al.mixedC min treatment failure 1 Joshi, 39 ICAAC, San Francisco, 1999, abstract 1201

Treatment outcome by subset of efavirenz concentration windows in studies /004/005/021/024 Number of Patients (%) C 24 <3.5 µMC 24  3.5 µMTotal Failure17 (63%)20 (21%)37 (30%) Non-Failure10 (37%)77 (79%)87 (70%) Total These data show that treatment failure was three times as frequent (63% versus 21%) when EFV C 24 <3.5 µM Joshi, 39 ICAAC, San Francisco, 1999, abstract 1201

Efavirenz Efavirenz and virologic efficacy Limited data on retrospective relationships between efavirenz pharmacokinetics and treatment failure are available. Reported pharmacokinetic parameter is the C min.

Variability of exposure Example of variability of exposure (AUC) after administration of the same dose in a patient population.

Relevance of exposure Wild type

Decreased sensitivity Relevance of exposure

Wild type

Resistant Relevance of exposure

C min /IC 50 ratios If used, the threshold values for C min /IC 50 ratios should be established for each drug. Correcting for protein binding is a step in the right direction, but is also insufficient. Other factors such as penetration of compartments, intracellular accumulation, active metabolites, synergy/antagonism etc. should be taken into account.

C min /IC 50 ratios For the NNRTIs, the ratios that are required may well be > 500 For PIs, the required ratios may actually be smaller than 1 (intracellular accumulation) C min /IC 50 ratios can most likely not be used to compare the potency/durability of drugs

From in vitro to in vivo? Protein binding P-glycoprotein Accumulation Sanctuaries Active metabolites What else? Viral diversity Synergy

IC 50 versus EC 50 The IC 50 represents the concentration of a drug that is required for 50% inhibition of viral replication in vitro (can be corrected for protein binding etc). The EC 50 represents the plasma concentration/AUC required for obtaining 50% of the maximum effect in vivo.

Conclusions (1) For the protease inhibitors PK-PD relationships have been established (but not always). It is unclear which PK parameter should be used for each PI. Until now, PK-PD relationships have mainly been found for single PI-therapy (+/- 2 NRTIs).

Conclusions (2) For the NNRTIs indications of PK-PD relationships have been reported. It is unclear which PK parameter should be used. These relationships might rather be explained by the presence of resistant mutants than the ratio between exposure/IC 50 for wild-type virus.

Remarks (1) Models of PK-PD have largely not (yet) included sensitivity of the virus as a parameter. When linking phenotypic data with pharmacokinetics: IC 50 values should (if at all) rather be used than IC 90 or IC 95 values. EC values should rather be established than IC values. It would be interesting to know if the boosted PI-strategy overcomes the PK-PD relationships found with the unboosted strategy.

Remarks (2) Based on PK-PD relationships, pharmacokinetic data can and should be used as a background for new formulations/dosing regimens, but clinical data are still essential given the modest information available at this moment.

Acknowledgements Slotervaart Hospital, Amsterdam Agnes Veldkamp Monique de Maat Rolf van Heeswijk Joke Schol Monique Profijt Rikkert van der Put Ingrid Bedeker Hanneke Paap Lilian van Belle Slotervaart Hospital, Amsterdam Eric van Gorp Jan-Willem Mulder Pieter Meenhorst Jos Beijnen NATEC, University of Amsterdam Gerrit-Jan Weverling Joep Lange