Browsing by Author "Sawyer, James"

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    Apricitabine: A Novel Deoxycytidine Analogue Nucleoside Reverse Transcriptase Inhibitor for the Treatment of Nucleoside-Resistant HIV Infection
    (2007-04) Wainberg, Mark A; Cahn, Pedro; Bethell, Richard C; Sawyer, James; Cox, Susan
    Existing nucleoside reverse transcriptase inhibitors for HIV disease are limited by problems of resistance and, in some cases, long-term toxicity. Apricitabine (ATC; formerly BCH10618, SPD754 and AVX754) is a deoxycytidine analogue nucleoside reverse transcriptase inhibitor in clinical development. ATC retains substantial in vitro activity against HIV-1 containing many mutations associated with nucleoside reverse transcriptase inhibitor resistance, showing a less than twofold reduction in susceptibility in the presence of either up to five thymidine analogue mutations or the M184V mutation. ATC showed a low potential for cellular or mitochondrial toxicity in vitro. ATC is well absorbed orally, with a bioavailability of 65–80%. Its plasma elimination half-life (approximately 3 h), and the intracellular half-life of its triphosphate (TP) metabolite (6–7 h) support twice-daily dosing. Intracellular ATC-TP levels are markedly reduced in the presence of lamivudine or emtricitabine, indicating that clinical co-administration of ATC together with these agents will not be possible. The drug is renally eliminated, giving a low potential for hepatic drug interactions. In a double-blind, randomized, placebo-controlled Phase II monotherapy trial in antiretroviral-naive patients, ATC doses of 1,200 and 1,600 mg/day reduced plasma viral load levels by 1.65 and 1.58 log10 HIV RNA copies/ml, respectively, after 10 days of treatment (P<0.0001 versus placebo). ATC showed a low propensity to select for resistance mutants in vitro and during clinical monotherapy. ATC was well tolerated in volunteers and in HIV-infected patients. This promising profile suggests that ATC may be useful in treating patients who have failed previous lamivudine- or emtricitabine-containing regimens. Further studies to evaluate the long-term efficacy and tolerability of ATC are underway.
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    Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naive, HIV-infected patients
    (2006-06-12) Cassetti, Isabel; Wood, Robin; Phanuphak, Praphan; Shiveley, LeeAnn; Bethell, Richard C; Sawyer, James
    Objective: Apricitabine (formerly AVX754 and SPD754) is a deoxycytidine analogue nucleoside reverse transcriptase inhibitor in clinical development for patients with HIV disease. This study evaluated the antiretroviral efficacy, tolerability and safety of apricitabine monotherapy, administered for 10 days in antiretroviral-naive, HIV-1 infected adults. Methods: Adult patients (≥ 18 years) with HIV infection (CD4 count ≥ 250 cells/μl; plasma HIV-1 RNA level 5000–100 000 copies/ml) were randomized to 10 days' double-blind oral therapy with placebo or apricitabine 400 mg/day, 800 mg/day, 1200 mg/day, or 1600 mg/day. Results: At 7 days, all apricitabine doses produced statistically significant log10 reductions in plasma HIV RNA levels from baseline relative to placebo (n = 13; P < 0.0001), as follows: −1.16 (400 mg; n = 11), −1.28 (800 mg; n = 12), −1.44 (1200 mg; n = 14), −1.30 (1600 mg; n = 13). After 10 days, the log10 viral load reductions with apricitabine 1200 mg (−1.65; P = 0.01) and 1600 mg/day (−1.58; P = 0.04) were significantly greater than that with the 400-mg dose (−1.18). No clinically relevant changes were observed in CD4 or CD8 cell indices. Apricitabine was well tolerated and showed no tendency to select any particular resistance mutation. Conclusion: Apricitabine monotherapy showed promising antiretroviral efficacy, good tolerability and a low propensity for resistance selection in antiretroviral-naive HIV-infected patients treated for 10 days. These results warrant further evaluation of the long-term clinical efficacy and tolerability of apricitabine.
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    Multiple-Dose Pharmacokinetics of Apricitabine, a Novel Nucleoside Reverse Transcriptase Inhibitor, in Patients with HIV-1 Infection
    (2008) Cahn, Pedro; Rolón, María José ; Cassetti, Isabel; Shiveley, LeeAnn; Holdich, Tom; Sawyer, James
    Background and objective: This study aimed to investigate the multiple-dose pharmacokinetics of apricitabine, a novel deoxycytidine analogue reverse transcriptase inhibitor, in antiretroviral-naive patients with HIV-1 infection. Methods: This was an international, randomized, double-blind, placebo-controlled, multicentre, dose-ranging study. Patients received 10 days' oral placebo or apricitabine 200, 400, 600 or 800 mg twice daily or 800 or 1200 mg once daily. On days 1 and 8, blood and urine samples were collected over 24 hours for pharmacokinetic analysis. Apricitabine triphosphate pharmacokinetics were investigated in peripheral blood mononuclear cells (PBMCs) on day 8. Results: Overall, 63 patients (mean age 33.9 +/- 8.7 years; mean weight 71.6 +/- 15.4 kg) were randomized, and 62 patients completed the study. Apricitabine was rapidly absorbed, with peak plasma concentrations attained within approximately 1.5-2.5 hours. Pharmacokinetics were linear over the range 200-800 mg twice daily. Apricitabine was predominantly excreted via the kidneys, with no significant accumulation during repeated administration. Steady-state conditions were attained by day 8. Apricitabine triphosphate exposure in PBMCs was roughly proportional to the dose of apricitabine across the dose range 200-800 mg twice daily, with adequate correlations between plasma exposure to apricitabine (9910 ng/mL per 65 kg for 800-mg twice-daily administration) and PBMC exposure to apricitabine triphosphate (maximum concentration [C(max)] = 5.55 +/- 1.94 pmol/million cells for 800-mg twice-daily administration). Apri-citabine was well tolerated. Conclusion: Apricitabine shows essentially linear pharmacokinetics during repeated administration in patients with HIV-1 infection.