# Presentation: 001907

## 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
-  		**	****pretreatment****	****PK parameters****	****PD parameters**
- Stein *et al.*	NRTIs		AUC, Cmin	 HIV-1 RNA wk 24
- Burger *et al.*	mixed		conc. ratio	 HIV-1 RNA wk 24
- Harris *et al.*	NRTIs		Cmin		1-NAUC (RNA) wk 24
- Fletcher *et al.**	*NRTIs		Cmin		 HIV-1 RNA wk 24
- Murphy *et al.*	NRTIs/naïve	AUC, Cmin, Cmax	 HIV-1 RNA day 36
- Acosta *et al.**	*naïve		AUC, Cmin	HIV-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, Cmin, and Cmax (all correlated).
- No clear data on such relationships when indinavir is used in combination with (low dose) ritonavir.

## Indinavir

- Indinavir and (renal) toxicity
-  		**	****pretreatment****	****PK parameters****	****PD parameters**
- Dieleman *et al.*	NRTIs		conc. ratio	urological 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 Cmax 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 Cmax might be the main determinant of renal toxicity1.

- 1Gatell, 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
-  		**	****pretreatment****	****PK parameters****	****PD parameters**
- Gieschke *et al.*	naïve (monother)	AUC		 HIV-1 RNA wk   8
- Hoetelmans *et al.*	mixed		conc. ratio	 HIV-1 RNA wk 48
- Hoetelmans *et al.**	*naïve (quadruple)	conc. ratio	initial 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 Cmin (all correlated).
- No clear data on such relationships when saquinavir is used in combination with (low dose) ritonavir.

## Saquinavir

- Saquinavir and toxicity
-  		**	****pretreatment****	****PK parameters****	****PD parameters**
- Reijers *et al.*	naive		conc. ratio	gastrointestinal 							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
-  		**	****pretreatment****	****PK parameters****	****PD parameters**
- Kerr *et al.**	*	naïve (triple)	2h conc.		HIV-1 RNA wk 24
- Hoetelmans *et al.**	*naïve (quadruple)	conc. ratio	initial 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
-  		**	****pretreatment****	****PK parameters****	****PD parameters**
- Reijers *et al.*	naive		conc. ratio	gastrointestinal 							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
-  		**	****pretreatment****	****PK parameters****	****PD parameters**
- Gatti *et al.*	naive		Cmax, Cmin	gastrointestinal 							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, Cmax and Cmin (all correlated).

## Nevirapine

- Nevirapine and virologic efficacy
-  		**	****pretreatment****	****PK parameters****	****PD parameters**
- Veldkamp *et al.*	naïve		median 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
-  		**	****pretreatment****	****PK parameters****	****PD parameters**
- Joshi *et al.*	mixed		Cmin		treatment failure

- 1Joshi, 39 ICAAC, San Francisco, 1999, abstract 1201

## Treatment outcome by subset of efavirenz concentration windows in studies 266-003/004/005/021/024

- 	                    Number of Patients (%)
- 	C24 <3.5 μM	C24 3.5 μM	Total
- Failure	17 (63%)	20 (21%)	37 (30%)
- Non-Failure	10 (37%)	77 (79%)	87 (70%)
- Total	27	97	124
- These data show that treatment failure was three times as frequent(63% versus 21%) when EFV C24 <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 Cmin.

## Variability of exposure

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

## Relevance of exposure

- Wild type

## Relevance of exposure

- Wild type

- Decreased
- sensitivity

## Relevance of exposure

- Wild type

## Relevance of exposure

- Wild type

- Resistant

## Cmin/IC50 ratios

- If used, the threshold values for Cmin/IC50 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.

## Cmin/IC50 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)
- Cmin/IC50 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**

## IC50 versus EC50

- The IC50 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 EC50 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/IC50 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: IC50 values should (if at all) rather be used than IC90 or IC95 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