Pharmacokinetics of Saquinavir hard gel (Invirase) when combined with Atazanavir

1. The 4th International Workshop on Clinical Pharmacology of HIV Therapy 8.11 Pharmacokinetics of Saquinavir hard gel (Invirase) when combined with Atazanavir D Prelutsky1, P Salvato2, R Falcon3 1. Washington University School of Medicine, St. Louis, MO, USA; 2. Diversified Medical Practices , Houston, TX, USA; 3. RocheLaboratories, Nutley, NJ, USA Table 1: Baseline Characteristics Abstract At the Houston site of this observational study, several patients had initiated treatment with Atazanavir 400mg qd & Saquinavir hard gel (Invirase) 600mg tid. Cmin Saquinavir levels were assessed. For patient convenience the dose of Saquinavir was switched to 1600mg once daily and Cmin levels were repeated after at least 14 days on the new therapy. Background: Previous studies have demonstrated similar Mean Cmin 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 Cmin 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 Cmin values. Patients receiving 1600mg Invirase QD had Mean and Median Cmin values of 153 and120ng/ml. Conclusions: In this limited observational study, Invirase, when given with Atazanavir, resulted in Cmin levels which indicate that Atazanavir acts as a significant pharmacokinetic booster of Invirase. 7 of 11 patients achieved a Cmin level above the EC50 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). Table 4: Saquinavir-hgc (Invirase) pre dose Cmin levels **: drawn late at 29 hours post dose. Value censored for statistical analysis Limitations Background Due to the paucity of data of this combination therapy in HIV infected individuals, random Cmin 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. 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. • 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 T½, 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 Cmax, AUC and Cmin 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 Cmin 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. Table 2: Saquinavir-hgc (Invirase) random pre-dose Cmin levels Conclusions  • In this limited observational study, Invirase, when given with Atazanavir, resulted in Cmin levels, which indicate that Atazanavir acts as a significant pharmacokinetic booster of Invirase. • 7 of 11 patients achieved a Cmin level above the EC50 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)    In follow up, some patients were evaluated more comprehensively with Saquinavir Cmax levels drawn 3 hours after an observed dose, followed by Cmin levels 24 hours after the observed dose. Methods Table 3: Patients with Cmin and Cmax values during directly observed (DOT) dosing cycle References • 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 9th Conference on Retroviruses and Opportunistic Infections • (Abstract S29e). Seattle. Feb 24-28, 2002. • 2. The 3rd International Workshop on Clinical Pharmacology of HIV Therapy (Abstract MoPp B2007). Washington DC. April 2002. • 3. The 7th Conference on Retroviruses and Opportunistic Infections • (Abstract 504). San Francisco, CA. Jan 30 - Feb 2, 2000. Contact Ron Falcon MD Roche Laboratories Inc. 340 Kingsland Street Nutley, NJ 07110 USA E-Mail: ron.falcon@roche.com *: value counted as 0 ng/ml for statistical analysis