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Evaluation of steady‐state pharmacokinetic interactions between ritonavir‐boosted BILR 355, a non‐nucleoside reverse transcriptase inhibitor, and lamivudine/zidovudine in healthy subjects
Author(s) -
Huang F.,
Allen L.,
Huang D. B.,
Moy F.,
Vinisko R.,
Nguyen T.,
Rowland L.,
MacGregor T. R.,
Castles M. A.,
Robinson P.
Publication year - 2012
Publication title -
journal of clinical pharmacy and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.622
H-Index - 73
eISSN - 1365-2710
pISSN - 0269-4727
DOI - 10.1111/j.1365-2710.2010.01235.x
Subject(s) - lamivudine , zidovudine , ritonavir , reverse transcriptase inhibitor , nucleoside reverse transcriptase inhibitor , virology , pharmacokinetics , reverse transcriptase , nucleoside analogue , nucleoside , human immunodeficiency virus (hiv) , pharmacology , medicine , chemistry , virus , sida , viral load , viral disease , rna , antiretroviral therapy , stereochemistry , biochemistry , hepatitis b virus , gene
Summary What is known and Objective: BILR 355 is a second generation non‐nucleoside reverse transcriptase inhibitor. It has shown promising in vitro anti‐HIV‐1 activities and favourable human pharmacokinetic properties after co‐administration with ritonavir (RTV). Lamivudine (3TC) is a nucleoside reverse transcriptase inhibitor. It is excreted predominantly in urine by a transporter‐mediated pathway. These two drugs are likely to be given together to HIV‐infected patients. The objective of this study was to investigate any steady‐state pharmacokinetic interactions between RTV‐boosted BILR 355 and 3TC/zidovudine (ZDV). Methods: This was a randomized, open label, prospective study. In group A, 39 healthy subjects were given 3TC/ZDV (150 mg/300 mg) twice daily (b.i.d.) for 7 days, and then BILR 355 and RTV (BILR 355/r, 150 mg/100 mg) were co‐administered with this regimen for an additional 7 days. Intensive blood samples were taken on days 7 and 14 for pharmacokinetic assessments. In group B, 12 healthy subjects were given BILR 355/r (150 mg/100 mg) b.i.d. for 7 days. The pharmacokinetic data from group B were pooled with data from group B subjects in other similar studies performed in parallel (BILR 355 alone group in BILR 355 drug–drug interaction studies with tipranavir, lopinavir/RTV, and emtricitabine/tenofovir DF; BILR 355 regimen was the same). Results and Discussion: After co‐administration with BILR 355/r, the AUC 12,ss and C max,ss of 3TC increased by 45% and 24%, respectively; the elimination half‐life ( t 1/2 ,ss) of 3TC was significantly increased. However, the pharmacokinetics of ZDV was unchanged. Co‐administration with 3TC/ZDV resulted in a 22% decrease in AUC 12,ss and a 20% decrease in C max,ss for BILR 355. The observed increase in exposure and prolongation of t 1/2,ss of 3TC is potentially related to inhibition of OCT‐mediated urinary excretion of 3TC. What is new and Conclusion: Concomitant administration of BILR 355 with 3TC/ZDV resulted in a modest decrease in exposure to BILR 355 and a 45% increase in exposure to 3TC.