1. Charge to the Committee Kimberly Struble, Pharm.D. Regulatory Review Officer Division of Antiviral Drug Products

2. New Formulations or Regimens Current Recommendations Types of Data to Support Approval: – –Bioequivalence - similar PK profiles – –PK data in setting of well defined exposure response relationship – –Clinical efficacy and safety - different PK profiles and exposure response relationship unknown/unclear

3. New Regimens Efficacy Studies Recent Examples – –48 week trials including 500-700 patients (with 24 week interim analyses) Nelfinavir BID regimen DDI QD regimen Need to streamline the amount of data required to support the marketing of new regimens/formulations of approved drugs

4. Considerations Clinical trial + supportive PK/PD informationClinical trial + supportive PK/PD information –May be possible to enroll fewer subjects –Duration of trials?? –Longer trials may be necessary New regimens/formulations where all exposure measures increasedNew regimens/formulations where all exposure measures increased –design a trial powered for safety considerations

5. Goals Create a guidance document for IndustryCreate a guidance document for Industry –Use of PK/PD data to support approval of new regimens/formulations –Trial size and duration –Guidelines for placing drug interaction information in labels - when is additional clinical and/or safety data necessary –Implications for pediatrics

6. Questions to Committee PK/EfficacyPK/Efficacy PK/SafetyPK/Safety Drug InteractionDrug Interaction PediatricPediatric Future ResearchFuture Research

7. PK/Efficacy Issues

8. PK and Response Protease Inhibitors:Protease Inhibitors: –APV - Cmax, Cmin –IDV - AUC, Cmax, Cmin –NLV - Cmax, Cmin –SQV - AUC, Cmin NNRTIs:NNRTIs: –EFV - Cmin –NVP - median concentration –Emivirine - AUC, Cmin NRTIS:NRTIS: –Tenofovir - AUC

9. PK/Efficacy Issues 1. What is the role of PK data in the evaluation of new formulations and alternative dosing regimens for approved antiretroviral drugs? Given the available data, please discuss the strengths and limitations of specific exposure measures, such as AUC and C min or other measures, in predicting virologic response. Given the available data, please discuss the strengths and limitations of specific exposure measures, such as AUC and C min or other measures, in predicting virologic response.

10. PK/Efficacy Issues 1A. What data are needed to rule out the relevance of any specific exposure measure to efficacy? 1B. What is the role of intracellular concentrations in the evaluation of new formulations and alternative dosing regimens for approved NRTIs? 1C. In what circumstances would clinical efficacy data be necessary?

11. PK/Efficacy Issues PK and virologic response relationships have mainly been evaluated in antiretroviral naïve patientsPK and virologic response relationships have mainly been evaluated in antiretroviral naïve patients –Prior approvals with efficacy, safety and PK data have focused on naïve patients 1D.Are these relationships applicable to treatment experienced patients? Are there cases where additional PK and/or efficacy data are necessary for different patient populations?

12. PK/Safety Issues

13. PK and toxicity Protease Inhibitors:Protease Inhibitors: –APV - Cmax –IDV - AUC, Cmax –SQV - concentration ratio –RTV - AUC, Cmax, Cmin NRTIsNRTIs –ABC - AUC, Cmax

14. PK/Safety Issues 2.Do the scientific data at present correlate any particular exposure measure with toxicity?

15. PK/Safety Issues Change in formulation/dosing regimen or drug interaction may increase all exposure measuresChange in formulation/dosing regimen or drug interaction may increase all exposure measures Additional safety information is required to ensureAdditional safety information is required to ensure increased concentrations are not associated with additional risks or an objectionable tolerability profile

16. PK/Safety Issues Fortovase exampleFortovase example –Increased bioavailability –Increased total daily dose –Both Safety and Efficacy Issues Required safety database of approx 500 patients followed for 16-24 weeksRequired safety database of approx 500 patients followed for 16-24 weeks Required clinical study comparing efficacy of Invirase vs FortovaseRequired clinical study comparing efficacy of Invirase vs Fortovase

17. PK/Safety Issues Ensure increases in certain parameters are not associated with objectionable tolerability profilesEnsure increases in certain parameters are not associated with objectionable tolerability profiles IDV/RTV Example 800/100 and 800/200 mg BID widely used800/100 and 800/200 mg BID widely used  AUC, Cmax = impact on safety (??)

18. PK/Safety Issues 3.What amount and duration of safety data are needed to support new formulations/new dosing regimens of approved antiretroviral drugs with increased exposure measures?

19. Drug Interaction Issues

20. PK Enhancers:PK Enhancers: –No information in labels re: PK enhancer (e.g. subtherapeutic doses of ritonavir) + PI –Preliminary data on certain interactions show increase in AUC and Cmin and decrease in Cmax 4.Which exposure measures should be considered when providing labeling information on concomitant administration of antiretrovirals?

21. Drug Interaction Issues 4A.If one or more exposure measures are decreased should additional clinical data be required? If so, how much? Are there other circumstances in which clinical data are necessary?

22. Different Dosing Possibilities IDV 800 mg BID +IDV 800 mg BID + –RTV 100 mg BID –RTV 200 mg BID SQV 1200 mg QD +SQV 1200 mg QD + –RTV 100 or 200 mg QD SQV 1600 mg QD +SQV 1600 mg QD + –RTV 100 mg QD SQV 1800 mg QD +SQV 1800 mg QD + –RTV 100 mg QD SQV 1000 mg BIDSQV 1000 mg BID –RTV 100 mg BID APV 450 mg BID + –RTV 100 mg BID –RTV 300 mg BID APV 600 mg BID + –RTV 100 mg BID –RTV 300 mg BID APV 900 mg BID + –RTV 200 mg BID APV 1200 mg QD + –RTV 200 mg QD

23. Drug Interaction Issues: 4B.How should several dosing possibilities be addressed in labels? What criteria should be used for placing specific recommendations in labels?

24. Pediatric Issues

25. Pediatric Issues: Dosing Recommendations NelfinavirNelfinavir –Original dosing recommendations in children > 2 years based on similar AUC, Cmax, Cmin as seen in adults For some antiretrovirals all exposure measures may not be similar for adults and childrenFor some antiretrovirals all exposure measures may not be similar for adults and children –Clearance may be greater in younger children, therefore may not be feasible to match all exposure measures

26. Pediatric Issues 5.Once an alternate regimen has been identified in adults, should we require identical PK profiles in children (i.e., all exposure measures equivalent) or only equivalent critical parameters (i.e., AUC or Cmin)? Does this apply to all drugs and all pediatric sub-populations or are there some situations in which more clinical/virologic data will be necessary?

27. Future Research

28. Future Research Issues 6.What kinds of studies are needed to better define PK/PD relationships for antiretrovirals?