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Pre-Clinical and Clinical Investigation of Pharmacokinetic and Pharmacodynamic Interactions Between Darunavir, a Novel Protease Inhibitor and Rosuvastatin

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Title: Pre-Clinical and Clinical Investigation of Pharmacokinetic and Pharmacodynamic Interactions Between Darunavir, a Novel Protease Inhibitor and Rosuvastatin
Author : Divya Samineni
Release Date : January 18, 2013
Genre: Medical,Books,Professional & Technical,
Pages : * pages
Size : 15062 KB

Description

Treatment of dyslipidemia in HIV-infected persons is commonly required with the use of protease inhibitors (PIs) which may be restricted by drug-drug interactions between antiretroviral agents and statins. We hypothesized that darunavir/ritonavir (DRV/rtv) modulate the pharmacokinetics of rosuvastatin (RSV) when co-administered by altering its hepatic disposition. The plausible genetic influence on the plasma exposure of RSV was also explored.To investigate this hypothesis, we first conducted a clinical drug interaction study and subsequently performed in vitro correlative/mechanistic analysis. In the open label, crossover study, 12 healthy volunteers were randomized to receive either RSV 10 mg/day or DRV/rtv 600/100 mg (bid) and in combination for 7 days followed by a crossover to the other regimen for 7 more days. The fasting lipids were obtained at baseline and on days 7, 21 and 35 along with intensive PK sampling for 24 hours post-dose. The PK parameters such as Cmax, t1/2 and AUC0-24 were determined by non-compartmental analysis using WinNonLin 5.2. Statistical analyses were performed using Paired t test. Drug levels were compared with OATP1B1 c.521T > C, 388A>G, BCRP c.421 C > A, MRP2 c. -24C>T, 1249G>A, 3972C>T single nucleotide polymorphisms (SNPs) to investigate potential outliers in the drug interaction study. Next we assessed the influence of DRV on the activity of multidrug transporters OATP1B1, BCRP and Pgp in the transporter over-expressing CHO and MDCK cells and primary human hepatocyte cultures.The AUC0-24 and Cmax of RSV before and after administration of DRV/rtv showed a significant increase by 1.48 fold ( P=0.003) and 2.44 fold (P<0.001) without a change in the t1/2 (P=0.176). However the AUC, Cmax, and t1/2 of DRV and RTV were unaltered. The total cholesterol increased by a median 4% (P=0.002) when RSV was given in combination than when given alone. Furthermore, we observed a trend toward lower plasma exposure of RSV in subjects with OATP1B1 *1a/*15 than OATP1B1*1a/*1a genotypes. And no adverse events were attributable to the drug interaction. Our in vitro findings suggest that DRV/rtv led to an inhibition of OATP1B1 (IC50 = 10 µM) and BCRP (IC50 = 77 µM) and an induction in Pgp activity (p= 0.05)Co-administration of DRV/rtv significantly increased the plasma exposure of RSV and consequently led to a decline in the lipid-lowering effects of RSV. This study warrants large-scale interaction in HIV-infected population.