Pharmacokinetic (PK) Evaluation of Darunavir/Ritonavir (DRV/r) and Raltegravir (RAL) in Healthy Subjects
Reported by Jules Levin
ICAAC/IDSA Oct 28 2008 Wash DC
MS Anderson,1 V Sekar,2 F Tomaka,2 J Mabalot,1 R Mack,2 L Lionti,1 S Zajic,1 L Wenning,1 C Vanden Abeele,3 M Zinny,4 NM Lunde,5 B Jin,1 JA Wagner,1 M Iwamoto1
1Merck & Co., Inc., Whitehouse Station, NJ, 2Tibotec, Inc., Yardley, PA, 3Tibotec BVBA, Mechelen, Belgium, 4Promedica Clinical Research Center, Inc., Boston, MA, 5Prism Research, St. Paul, MN.
Multiple oral doses of 400-mg RAL given in combination with 600-mg DRV plus 100-mg RTV in healthy subjects resulted in a common adverse experience of rash.
Based on limited PK data, coadministration of DRV/r and RAL resulted in a modest effect on RAL with no clinically important changes in DRV pharmacokinetics.
Background: Both DRV/r, a next generation PI, and RAL, an InSTI, have separately demonstrated potent clinical activity in HIV-infected patients. This study evaluated the effect of co-administration of DRV/r and RAL on PK and safety in healthy subjects.
Methods: Eighteen healthy subjects were enrolled in an open-label, sequential 2-period study. In Period 1, all subjects were administered 400 mg RAL q12hr for 4 days. In Period 2, subjects were administered 400 mg RAL + 600/100 mg DRV/r q12hr for 12 days. Period 2 immediately followed Period 1. Doses were administered with a meal.
Results: Eight subjects presented with a clinical adverse experience (AE) of rash. Seven were rated mild to moderate in intensity; one progressed to a serious adverse event of maculopapular rash. Onset occurred between Days 8 and 12 of Period 2 of concomitant dosing. Six subjects out of 18 completed the study, but constituted an insufficient data set from which to draw PK conclusions. However, based on limited data, DRV/r had only modest effect on mean RAL PK parameters. The geometric mean ratio (GMR) for RAL co-administered with DRV/r relative to RAL alone was 0.71 (90% CI: 0.38 to 1.33) for AUC12hr, 0.67 (0.33 to 1.37) for Cmax, and 1.38 (0.16 to 12.12), for C12hr, respectively. Summary DRV PK parameters of AUC12hr, Cmax, C12hr in the presence of RAL aligned closely to historical data reported in healthy subjects given DRV/r alone.
Conclusions: Contrary to clinical experience with the combination in HIV-infected patients, co-administration of RAL with DRV/r in healthy subjects resulted in a common adverse experience of rash. Based on limited PK data, a co-administration of DRV/r and RAL resulted in a modest effect on RAL with no clinically important changes in DRV pharmacokinetics.
⋅ Raltegravir (RAL) is a novel HIV-1 integrase inhibitor with potent in vitro and clinical activity against HIV-1.
⋅ RAL is primarily metabolized by glucuronidation and has no inhibitory or inductive potential on CYP enzymes.
⋅ Darunavir (DRV) is a novel PI with potent in vitro and clinical activity against HIV-1.
⋅ DRV and ritonavir (RTV) are each metabolized primarily by CYP3A. DRV in combination with RTV is a net inhibitor of CYP3A.
⋅ An evaluation for a drug interaction between RAL and DRV/r was conducted as HIV-infected patients are likely to benefi t from combination administration.
⋅ Safety and tolerability were assessed by measurements of semirecumbent heart rate and blood pressure, ECG, laboratory safety tests (CBC, chemistry panel, urinalysis), and physical examinations.
⋅ Adverse experiences were evaluated as to their intensity, seriousness, and relationship to study drug.
Analytical and Pharmacokinetic Methods
⋅ Plasma samples were analyzed for RAL concentrations using a validated HPLC - MS/MS assay.
⋅ Plasma samples were analyzed for DRV and RTV concentrations using a validated HPLC - MS/MS assay.
⋅ C max and Tmax determined by inspection.
⋅ AUC 12hr calculated using linear up/log down trapezoidal method.
⋅ Confidence intervals for RAL and DRV C12hr, AUC12hr and Cmax were constructed using the appropriate mixed-effects linear model.
RAL ± DRV/r in Healthy Subjects
Clinical Adverse Experiences - Summary
10 subjects reported a total of 16 clinical non-serious adverse experiences (AEs) and 1 serious adverse experience (SAE):
-- All non-serious AEs except 1 were considered to be drug-related
-- All non-serious AEs were rated mild to moderate in intensity
-- The SAE was rated as "severe"
The most common drug-related clinical adverse experiences (reported by >/=2 subjects) were rash and headache:
-- 2 non-serious AEs of headache were reported and ranged in intensity from "mild" to "moderate"
-- A total of 8 adverse experiences of rash were reported:
⋅ 7 subjects with non-serious AEs of rash (2 pruritic)
⋅ Non-serious rashes ranged in duration from 11 days to 33 days
⋅ 1 subject with a SAE of maculo-papular rash - subject recovered fully
- 12 subjects were discontinued
⋅ 2 subjects withdrew consent
- 6 subjects were discontinued due to a clinical AE of rash
⋅ All rashes had an onset during co-administration of RAL and DRV/r in Period 2 between Day 8 and Day 12; subjects were discontinued on the same or next day
- Due to the incidence of rash, the study was not further enrolled; The PI discontinued 4 subjects
RAL ± DRV/r in HIV-Infected Subjects - Safety Summary
In phase III studies of treatment-experienced patients with HIV infection, after at least 48 weeks of therapy, among a subset of 301 patients who received RAL (N=200) or placebo (N=101) in combination with DRV/r as part of the optimized background therapy (OBT)
-- The occurrence of rash regardless of drug relationship was higher in patients receiving RAL + DRV/r in OBT compared with Placebo + DRV/r (15.0% vs 4.0%)
-- The occurrence of rash considered drug-related was similar in the RAL + DRV/r and Placebo + DRV/r groups (3.5% vs 2.0%)
-- None of the rashes was considered serious or led to discontinuation of therapy
-- NB: mean duration of follow up was longer overall for patients randomized to raltegravir versus placebo due to higher failure rate in placebo group
Effect of DRV/r on RAL Pharmacokinetics
Arithmetic Mean RAL Plasma Concentration Profiles Following Multiple Oral Doses of 400-mg RAL Twice Daily With or Without Co-administration of Multiple Oral Doses of 600-mg DRV and 100-mg RTV Twice Daily to Healthy Male and Female Subjects
Due to the incidence of rash, the study was not further enrolled. These subjects were not replaced.
Due to an insuffi cient number of evaluable subjects and greater than anticipated variability, no pharmacokinetic conclusions for the effect of DRV/r on RAL can be drawn from this study.
However, based on limited pharmacokinetic data, co-administration of DRV/r and RAL appears to result in a modest effect on RAL.
Mean DRV and RTV Plasma Pharmacokinetics Following Multiple Oral Doses of 400 mg RAL Twice Daily With or Without Co-administration of Multiple Oral Doses of 600 mg DRV and 100 mg RTV Twice Daily to Healthy Male and Female Subjects Compared to Historical Data for Co-administration of 600 mg DRV and 100 mg RTV Alone
1 Sekar V., El Malt M., De Paepe E., Mack R., De Pauw M., Vangeneugden T., Lefebvre E., Hoetelmans R. Effect of the HIV protease inhibitor darunavir (DRV), co-administered with low-dose ritonavir, on the pharmacokinetics of digoxin in healthy volunteers. ASCPT, Anaheim, CA, USA, 21-24 March 2007. Abstract PII-104.
2 Sekar V, Spinosa-Guzman S, De Paepe E, Stevens T, Tomaka F, De Pauw M, Hoetelmans RM. Pharmacokinetic interaction trial between darunavir in combination with low-dose ritonavir and didanosine. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, Australia, 22-25 July 2007.
These posters are available on-line at www.tibotec.com
In the presence of RAL, mean DRV C 12hr, Cmax and AUC12hr aligned closely to historical data reported in healthy subjects co-administered 600 mg DRV and 100 mg ritonavir b.i.d. alone.
These results are consistent with a report from the French expanded access program that includes an arm of 400 mg RAL b.i.d. co-administered with 600 mg DRV and 100 mg RTV b.i.d. (n=83) and which concludes that Despite a large interpatient variability, DRV/r combination had no deleterious effect on RAL Cmin.1
1 Long K., Soulie C., Schneider L., Ghosn J., Piketty C., Boue F., Reynes J., Raffi F., Calvez V., Katlama C., Peytavin G. Therapeutic Drug Monitoring of Raltegravir (MK-0518) in Experienced HIV-infected Patients. 11th European Aids Conference, October 24-27, 2007, Madrid, Spain.