1. Pharmacokinetics of Saquinavir hard gel (Invirase) when combined with Atazanavir 8.11 D Prelutsky 1, P Salvato 2, R Falcon 3 1. Washington University School of Medicine, St. Louis, MO, USA; 2. Diversified Medical Practices, Houston, TX, USA; 3. Roche Laboratories, Nutley, NJ, USA Background: Previous studies have demonstrated similar Mean C min values when Invirase or SQV soft gel (Fortovase) is boosted with Ritonavir 1,2. This has lead to increased interest in Invirase as the preferred formulation due to better tolerability. The pharmacokinetics of Atazanavir (ATV) with Fortovase have recently been described in healthy volunteers, showing a significant boosting effect of Atazanavir on Fortovase 3. Little is known about the pharmacokinetics of Atazanavir combined with Invirase in HIV-Infected adults. Methods: We are reporting a multi-center, observational study of 12 HIV infected patients taking varying doses of Invirase with 400mg of Atazanavir once daily with food. Doses of Invirase included 600mg TID, 1200mg QD, and 1600mg QD. Results: N=12, all male, mean age was 42 years, all prior antiretroviral treatment experienced. Mean CD4 88 (range zero-244). The Mean and Median C min levels for patients taking 1200mg Invirase QD were 309 and 250ng/ml respectively. With a dose of Invirase 600mg TID, we observed 143 and 160ng/ml for Mean and Median C min values. Patients receiving 1600mg Invirase QD had Mean and Median C min values of 153 and 120ng/ml. Conclusions: In this limited observational study, Invirase, when given with Atazanavir, resulted in C min levels which indicate that Atazanavir acts as a significant pharmacokinetic booster of Invirase. 7 of 11 patients achieved a C min level above the EC 50 of SQV of 50ng/ml. Formal PK studies will need to evaluate the optimal dose for the combination of Atazanavir with Saquinavir hard gel (Invirase). Abstract The use of protease inhibitors (PI) has evolved since their introduction. Commonly, protease inhibitors are pharmacokinetically boosted by coadministration with a cytochrome p450 cyp 3A4 inhibitor like Ritonavir. This combination leads to increases in PI exposure and T ½, allowing for more effective therapy with more convenient dosing. Ritonavir, while an effective boosting agent, has been associated with side effects such as hyperlipidemias and GI intolerance. Atazanavir is a new PI which is currently under review for market approval by health authorities. Atazanavir has shown the ability to boost Saquinavir soft gel (Fortovase) levels 5 to 6-fold when coadministered in healthy volunteers 3. O’Mara demonstrated C max, AUC and C min levels of 6589ng/ml, 30807 ng●hr/ml and 92ng/ml for healthy subjects taking Fortovase 1600mg with Atazanavir 400mg both dosed once daily. No data has ben published on the interaction of Saquinavir hard gel (Invirase) with Atazanavir or the interaction of Atazanavir with Saquinavir in HIV-infected patients. When boosting with Ritonavir, previous studies 1,2 have demonstrated similar Mean C min values when Saquinavir hard gel (Invirase) or Saquinavir soft gel (Fortovase) is given. This has lead to increased interest in Invirase as the preferred formulation due to better GI tolerability, smaller tablet size and easier storage. Background Methods PatientgenderAge (years) Baseline at initiation of ATV CD4 (cells/ml)HIV-RNA (copies/ml) St. Louis 1Male40244228,000 2Male4154477,000 3Male4264> 750,000 4Male41125> 750,000 5Male4223174,000 6Male521899,740 Houston 7Male3718> 750,000 8Male44145162,000 9Male417038,500 10Male5228540,000 11Male4196260,000 12Male360531,250 Table 1: Baseline Characteristics Due to the paucity of data of this combination therapy in HIV infected individuals, random C min Saquinavir levels were obtained in 4 patients at the St. Louis site. Significant inter-patient variability was observed. Adherence was assessed by patient interview and felt to be appropriate. Table 2: Saquinavir-hgc (Invirase) random pre-dose C min levels PatientATZ400 & SQV1200 mg qd 1700 ng/ml 2300 ng/ml 3200 ng/ml 438 ng/ml Median 250 ng/ml Mean 309 ng/ml In follow up, some patients were evaluated more comprehensively with Saquinavir C max levels drawn 3 hours after an observed dose, followed by C min levels 24 hours after the observed dose. PatientDose C max, drawn 3 hours post DOT dose C min, dawn 24 hours post DOT dose 1 ATZ 400 & SQV1200 mg qd 630 ng/ml<25 ng/ml* 2 ATZ 400 & SQV1200 mg qd 2200 ng/ml70 ng/ml 3 ATZ 400 & SQV1200 mg qd 547 ng/ml348 ng/ml 5 ATZ 400 & SQV1200 mg qd 50 ng/ml60 ng/ml 6 ATZ 400 & SQV1600 mg qd 993 ng/ml45 ng/ml Median 630 ng/ml Mean 884 ng/ml Median 60 ng/ml Mean 105 ng/ml Table 3: Patients with C min and C max values during directly observed (DOT) dosing cycle *: value counted as 0 ng/ml for statistical analysis At the Houston site of this observational study, several patients had initiated treatment with Atazanavir 400mg qd & Saquinavir hard gel (Invirase) 600mg tid. C min Saquinavir levels were assessed. For patient convenience the dose of Saquinavir was switched to 1600mg once daily and C min levels were repeated after at least 14 days on the new therapy. Table 4: Saquinavir-hgc (Invirase) pre dose C min levels Patient ATZ 400mg qd & SQV 600mg tid ATZ 400 & SQV 1600 mg qd 7180 ng/ml143 ng/ml 8160 ng/ml97 ng/ml 989 ng/ml298 ng/ml 10197 ng/mlnot available 1189 ng/ml23 ng/ml ** 12Not drawn74 ng/ml Median 160 ng/ml Mean 143 ng/ml Median 120 ng/ml Mean 153 ng/ml While the results of this observational study give an initial impression of the interaction of Atazanavir with Saquinavir hard gel (Invirase), drug levels obtained in routine patient care settings may be influenced by multiple factors including adherence, incorrect timing of dose and lack of standardized food intake. In addition the levels reported here were obtained from more than one laboratory. Limitations Conclusions In this limited observational study, Invirase, when given with Atazanavir, resulted in C min levels, which indicate that Atazanavir acts as a significant pharmacokinetic booster of Invirase. 7 of 11 patients achieved a C min level above the EC 50 for SQV of 50ng/ml. Formal PK studies are needed to further characterize the interaction between Invirase and Atazanavir. Does the boosting effect of Atazanavir on Saquinavir hard gel (Invirase) differ from the boosting effect on Saquinavir soft gel (Fortovase)? – Our data does not allow for a direct answer of this question. The interaction of Atazanavir and Fortovase was evaluated in formal PK in healthy individuals 3, while our data with Invirase was obtained in routine care settings in HIV-infected individuals. – Nevertheless the Saquinavir levels achieved in this cohort are significantly higher than those achieved by Invirase alone, supporting the claim of Atazanavir being a significant booster for Invirase. Formal PK studies will need to evaluate the optimal dose for the combination of Atazanavir with Saquinavir hard gel (Invirase) 1.The 9 th Conference on Retroviruses and Opportunistic Infections (Abstract S29e). Seattle. Feb 24-28, 2002. 2. The 3 rd International Workshop on Clinical Pharmacology of HIV Therapy (Abstract MoPp B2007). Washington DC. April 2002. 3. The 7 th Conference on Retroviruses and Opportunistic Infections (Abstract 504). San Francisco, CA. Jan 30 - Feb 2, 2000. References Contact Ron Falcon MD Roche Laboratories Inc. 340 Kingsland Street Nutley, NJ 07110 USA E-Mail: ron.falcon@roche.com **: drawn late at 29 hours post dose. Value censored for statistical analysis     Multi-center, observational study of 12 HIV infected patients, taking varying doses of Invirase with 400mg of Atazanavir once daily with food, along with nucleoside reverse transcriptase inhibitors. Patients on concomitant NNRTI therapy were excluded. Drug levels were obtained as part of routine medical care in HIV specialized care facilities in St. Louis and Houston, USA. All patients had been on therapy at least 14 days, ensuring levels were obtained at steady state. In some patients levels were repeated. For some levels, the medication dose was taken as observed therapy (DOT), followed by 3 hour post dose Cmax and 24 hour post dose Cmin levels. The St. Louis site used Quest diagnostics and Specialty labs. The Houston site used TDM labs The 4 th International Workshop on Clinical Pharmacology of HIV Therapy