ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Aug. 2007, p. 2982–2984 0066-4804/07/$08.00⫹0 doi:10.1128/AAC.00008-07 Copyright © 2007, American Society for Microbiology. All Rights Reserved.
Vol. 51, No. 8
Fosamprenavir plus Ritonavir Increases Plasma Ketoconazole and Ritonavir Exposure, while Amprenavir Exposure Remains Unchanged䌤 Mary B. Wire,1* Charles H. Ballow,2 Julie Borland,1 Mark J. Shelton,1 Yu Lou,1 Geoffrey Yuen,1 Jiang Lin,1 and Eric W. Lewis1 GlaxoSmithKline, Research Triangle Park, North Carolina,1 and Buffalo Clinical Research Center, Buffalo, New York2 Received 3 January 2007/Returned for modification 2 March 2007/Accepted 11 May 2007
Plasma ketoconazole (KETO), amprenavir (APV), and ritonavir (RTV) pharmacokinetics were evaluated in 15 healthy subjects after being treated with KETO at 200 mg once daily (QD), fosamprenavir (FPV)/RTV at 700/100 mg twice daily (BID), and then KETO at 200 mg QD plus FPV/RTV at 700/100 mg BID in this open-label study. The KETO area under the concentration-time curve at steady state was increased 2.69-fold with FPV/RTV. APV exposure was unchanged, and RTV exposure was slightly increased. angle Park, NC) using a validated analytical method based on protein precipitation, followed by high-pressure liquid chromatography–tandem mass spectrometry analysis. The lower limit of quantification for both APV and RTV was 0.010 g/ml, the maximum bias was 8.3% for APV and ⫺7.9% for RTV, the intraday precision was 11.4% for APV and 9.8% for RTV, and the interday precision was 3.2% for APV and 2.3% for RTV. A noncompartmental pharmacokinetic analysis of plasma KETO, APV, and RTV concentration-time data was conducted using WinNonlin Professional (version 4.1; Pharsight Corp., Mountain View, CA). The area under the curve over a dosing interval at steady-state (AUC0-), the maximum concentration (Cmax), and the concentration at the end of the dosing interval at steady-state (C) were estimated. The C was calculated based on the average of two predose samples. All statistical calculations were performed using SAS (version 8.2). Analysis of variance models, considering treatment as a fixed effect and subject as a random effect, were performed on logtransformed pharmacokinetic parameters to evaluate the impact of FPV/RTV on plasma KETO pharmacokinetics and the impact of KETO on APV and RTV pharmacokinetics. Ratios of geometric-least-squares means and associated 90% confidence intervals were estimated for the KETO, APV, and RTV pharmacokinetic parameters for the treatment comparisons of interest. Safety and tolerability were assessed by adverse events, clinical laboratory evaluations, and vital signs. Sixteen healthy adults gave written consent and fifteen subjects (nine males and six females) completed the study. One subject was withdrawn during period 2 due to a positive urine drug screen. Ages ranged from 18 to 52 years, and body weights ranged from 57 to 97 kg. The median steady state plasma KETO concentration-time profiles are displayed in Fig. 1. Plasma KETO, APV, and RTV pharmacokinetic parameters and treatment comparisons are summarized in Table 1. Coadministration of FPV/RTV at 700/ 100 mg BID and KETO at 200 mg QD increased the plasma KETO Cmax by 25% and increased the AUC0- 2.69-fold. Coadministration of FPV/RTV BID and KETO at 200 mg QD had no effect on plasma APV pharmacokinetics but increased the RTV AUC0- by 17% and Cmax by 13%. Study treatments were generally well tolerated over the 18
Fosamprenavir (FPV) is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) and a prodrug of amprenavir (APV). Ritonavir (RTV) is commonly coadministered with FPV to increase APV exposure. Identification of pharmacokinetic interactions between HIV-1 PIs and drugs for opportunistic infections is important for clinical management. Ketoconazole (KETO; Nizoral) is a synthetic broad-spectrum antifungal agent and a potent inhibitor of cytochrome P450 (CYP) 3A4. This study was designed to evaluate the effects of coadministering FPV/RTV at 700/100 mg twice daily (BID) and KETO at 200 mg once daily (QD) on steady-state plasma KETO, APV, and RTV pharmacokinetics. In this phase I, open-label, single-sequence, three-period study, healthy subjects received KETO at 200 mg QD for 4 days (period 1), followed by FPV/RTV at 700/100 mg BID for 10 days (period 2), followed by FPV/RTV at 700/100 mg BID plus KETO at 200 mg QD for 4 days (period 3). There was no washout between periods. The short duration (4 days) of coadministration of FPV/RTV with KETO in period 3 was selected to achieve steady-state pharmacokinetic conditions while minimizing the risk of significant transaminase elevations. Blood samples for the determination of KETO, APV, and RTV concentrations in plasma were obtained predose and at 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 16 (KETO only), and 24 (KETO only) h postdose for period 1, day 4 (KETO); period 2, day 10 (APV and RTV); and period 3, day 4 (APV, RTV, and KETO). Predose plasma KETO, APV, and RTV concentrations were determined on the 3 days prior to serial pharmacokinetic sampling to confirm the achievement of steady state. Samples were analyzed for KETO concentrations by highpressure liquid chromatography–tandem mass spectrometry analysis (PPD Development, Richmond, VA). The lower limit of quantification for KETO was 0.0500 g/ml, the maximum bias was ⫺3.75%, the intraday precision was 1.91%, and the interday precision was 1.16%. Samples were analyzed for APV and RTV concentrations by GlaxoSmithKline (Research Tri* Corresponding author. Mailing address: Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, 5 Moore Dr., 17.2231.2B, Research Triangle Park, NC 27709. Phone: (919) 483-5852. Fax: (919) 483-6380. E-mail:
[email protected]. 䌤 Published ahead of print on 21 May 2007. 2982
VOL. 51, 2007
NOTES
2983
FIG. 1. Median KETO concentration-time profiles after treatment with KETO at 200 mg QD alone (䡺) and in combination with FPV/RTV at 700 mg/100 mg BID (f) (n ⫽ 15).
days. All adverse events were of mild intensity, and the most frequently reported adverse events occurred during the 10-day FPV/RTV 700/100-mg BID treatment. These events included rash (four subjects [25%]), diarrhea (three subjects [19%]), nausea (three subjects [19%]), and headache and pain in the extremity (two subjects [13% each]). When stratified by body system, gastrointestinal (diarrhea and/or nausea) and skin (rash) adverse events appeared to be more common for the FPV/RTV combination than for the other two treatments. No subjects were withdrawn from the study due to adverse events. No vital signs or clinical laboratory abnormalities were reported as adverse events during the study. KETO is not widely used in clinical practice but is commonly studied in drug interaction trials because it is a potent inhibitor of CYP3A4, although it is less potent than RTV. As expected, the increase in plasma KETO exposure was greater for RTVboosted FPV than previously observed for unboosted APV. In a previous study, plasma KETO AUC0-⬁ increased 44% and
Cmax increased 19% when single doses of KETO at 400 mg and APV at 1,200 mg were coadministered (2). In addition, the 2.69-fold increase in plasma KETO AUC0- observed with FPV/RTV agrees with previous drug interaction studies that showed increased plasma KETO exposure when coadministered with RTV or RTV-boosted HIV-1 PIs. For example, coadministration of RTV at 500 mg BID increased the plasma KETO AUC0- 3.4-fold, and coadministration of lopinavir/RTV at 400/100 mg BID increased the plasma KETO AUC0- 3.0-fold (according to Kaletra and Norvir product information). In addition to the increased plasma KETO exposure we observed, plasma RTV AUC0- was slightly (17%) increased when FPV/RTV was coadministered with KETO. The RTV pharmacokinetic results also agree with previous drug interaction studies that showed increased plasma RTV exposure when coadministered with KETO. For example, coadministration of KETO at 200 mg QD with RTV at 500 mg BID increased the plasma RTV AUC0- by 18% and coadministration of KETO 200 mg at QD
TABLE 1. Steady-state plasma KETO, APV, and RTV pharmacokinetic parameter estimates and statistical comparison resultsa Pharmacokinetic parameter (n ⫽ 15)
Geometric mean (95% CI) [%CV]
Ratio of GLS means (90% CI)
Plasma KETO AUC0- (g 䡠 h/ml) Cmax (g/ml)
KETOb 16.6 (12.3–22.5) [59] 3.77 (2.99–4.74) [43]
FPV/RTV⫹KETOd 44.8 (34.2–58.6) [52] 4.71 (3.70–6.00) [46]
FPV/RTV⫹KETO vs KETO 2.69 (2.08–3.48) 1.25 (1.00–1.56)
Plasma APV AUC0- (g 䡠 h/ml) Cmax (g/ml) C (g/ml)
FPV/RTVc 35.9 (30.8–41.7) [28] 5.36 (4.57–6.30) [30] 2.12 (1.75–2.56) [35]
FPV/RTV⫹KETO 38.2 (31.9–45.7) [33] 5.88 (5.00–6.93) [30] 2.21 (1.89–2.58) [29]
FPV/RTV⫹KETO vs FPV/RTV 1.07 (0.98–1.16) 1.10 (0.98–1.23) 1.04 (0.97–1.12)
Plasma RTV AUC0- (g 䡠 h/ml) Cmax (g/ml) C (g/ml) a
FPV/RTV 5.23 (4.04–6.77) [49] 1.20 (0.87–1.66) [63] 0.195 (0.151–0.253) [49]
FPV/RTV⫹KETO 6.11 (4.79–7.79) [46] 1.36 (1.04–1.78) [51] 0.189 (0.139–0.257) [60]
CI, confidence interval; GLS, geometric least squares; %CV, percent coefficient of variation. KETO at 200 mg QD for 4 days. FPV at 700 mg BID plus RTV at 100 mg BID for 10 days. d FPV at 700 mg BID plus RTV at 100 mg BID plus KETO at 200 mg QD for 4 days. b c
FPV/RTV⫹KETO vs FPV/RTV 1.17 (1.03–1.33) 1.13 (0.93–1.38) 0.97 (0.83–1.12)
2984
NOTES
with SQV/RTV at 400/400 mg BID increased the plasma RTV AUC0- by 29% (1; Norvir product information, 2005). Plasma APV exposure was unchanged when FPV/RTV was coadministered with KETO in the present study. The APV pharmacokinetic results differ from the 31% increase in the plasma APV AUC0-⬁ observed when unboosted APV at 1,200 mg was coadministered with KETO at 400 mg (2), and these different results can be explained by the presence of the potent CYP3A4 inhibitor RTV in the FPV/RTV regimen, to which KETO does not provide any additional CYP3A4 inhibition effect on APV pharmacokinetics. Based on the results of this study, KETO doses greater than 200 mg QD are not recommended when coadministered with FPV/RTV at 700/100 mg BID because the plasma KETO
ANTIMICROB. AGENTS CHEMOTHER.
AUC0- was increased 2.69-fold. No change in the FPV/RTV dose is required when coadministered with KETO because plasma APV exposure was unchanged, and although plasma RTV exposures were not equivalent for the two treatments, AUC0- was only increased 17%. REFERENCES 1. Khaliq, Y. K. Gallicano, S. Venance, S. Kravcik, and D. W. Cameron. 2000. Effect of ketoconazole on ritonavir and saquinavir concentrations in plasma and cerebrospinal fluid from patients infected with human immunodeficiency virus. Clin. Pharmacol. Ther. 68:637–646. 2. Polk, R. E., M. A. Crouch, A. Pastor, W. Gouldin, D. S. Israel, B. M. Sadler, W. T. Symonds, Y. Lou, and G. E. Chittick. 1999. Pharmacokinetic interaction between ketoconazole and amprenavir after single doses in healthy men. Pharmacotherapy 19:1378–1384.
