Pharmacokinetics of the antimalarial drug, AQ-13, in rats and cynomolgus macaques.

The purpose of this study was to evaluate the bioavailability and pharmacokinetics of a new antimalarial drug, AQ-13, a structural analog of chloroquine (CQ) that is active against CQ-resistant Plasmodium species, in rats and cynomolgus macaques. Sprague-Dawley rats (n = 4/sex) were administered a single dose of AQ-13 intravenously (i.v.) (10 mg/kg) or orally (20 or 102 mg/kg). Blood and plasma samples were collected at several timepoints. AQ-13 achieved C(max) after oral administration at approximately 3 to 4 h and could be detected in blood for 2 to 5 days after oral administration. The ratio of area under the curve (AUC) values at the high and low dose for AQ-13 deviated from an expected ratio of 5.0, indicating nonlinear kinetics. A metabolite peak was noted in the chromatograms that was identified as monodesethyl AQ-13. Oral bioavailability of AQ-13 was good, approximately 70%. The pharmacokinetics of AQ-13 was also determined in cynomolgus macaques after single (i.v., 10 mg/kg; oral, 20 or 100 mg/kg) and multiple doses (oral loading dose of 50, 100, or 200 mg/kg on first day followed by oral maintenance dose of 25, 50, or 100 mg/kg, respectively, for 6 days). The AUC and C(max) values following single oral dose administration were not dose proportional; the C(max) value for AQ-13 was 15-fold higher following an oral dose of 100 mg/kg compared to 20 mg/kg. Monodesethyl AQ-13 was a significant metabolite formed by cynomolgus macaques and the corresponding C(max) values for this metabolite increased only 3.8-fold over the dose range, suggesting that the formation of monodesethyl AQ-13 is saturable in this species. The bioavailability of AQ-13 in cynomolgus macaques following oral administration was 23.8% for the 20-mg/kg group and 47.6% for the 100-mg/kg group. Following repeat dose administration, high concentrations of monodesethyl AQ-13 were observed in the blood by day 4, exceeding the AQ-13 blood concentrations through day 22. Saturation of metabolic pathways and reduced metabolite elimination after higher doses are suggested to play a key role in AQ-13 pharmacokinetics in macaques. In summary, the pharmacokinetic profile and metabolism of AQ-13 are very similar to that reported in the literature for chloroquine, suggesting that this new agent is a promising candidate for further development for the treatment of chloroquine-resistant malaria.

Pharmacokinetics in animals and humans of a first-in-class peptide deformylase inhibitor.

BB-83698, a potent and selective inhibitor of peptide deformylase, was the first compound of this novel antibacterial class to progress to clinical trials. Single- and/or multiple-dose studies with doses ranging from 10 to 50 mg of BB-83698/kg of body weight were done with mice, rats, and dogs. Intravenous pharmacokinetics were characterized by low to moderate clearances and moderate volumes of distribution for all species. In dogs, but not in rodents, central nervous system (CNS) effects were dose limiting for intravenously administered BB-83698 and were suspected to be related to a high maximum concentration of the agent in plasma (Cmax) rather than to total systemic exposure. Controlled infusion studies with dogs demonstrated that CNS effects could be avoided without compromising systemic exposure by reducing the Cmax. A randomized, double-blind, placebo-controlled, five-way-crossover, single-dose-escalation, phase I study to explore the safety, tolerability, and pharmacokinetics of intravenous BB-83698 at doses ranging from 10 to 475 mg was performed with healthy male volunteers. Systemic exposures were generally in linear relationships with administered doses in animals and humans. Pharmacokinetics were consistent, predictable, and exhibited good allometric scaling among all species (r2 >0.98). Moreover, BB-83698 dosing in humans proceeded to a predicted efficacious exposure (the area under the concentration-time curve/MIC ratio, up to 184) without any clinically significant adverse effects.

Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion.

In a phase 1 dose escalation study, 13 subjects with hemophilia A received by peripheral intravenous infusion a retroviral vector carrying a B-domain-deleted human factor VIII (hFVIII) gene. Infusions were well tolerated. Tests for replication competent retrovirus have been negative. Polymerase chain reaction (PCR) analyses demonstrate the persistence of vector gene sequences in peripheral blood mononuclear cells in 3 of 3 subjects tested. Factor VIII was measured in serial samples using both a one-stage clotting assay and a chromogenic assay. While no subject had sustained FVIII increases, 9 subjects had FVIII higher than 1% on at least 2 occasions 5 or more days after infusion of exogenous FVIII, with isolated levels that ranged from 2.3% to 19%. Pharmacokinetic parameters of exogenous FVIII infused into subjects 13 weeks after vector infusion showed an increased half-life (T1/2; P <.02) and area under the curve (AUC, P <.04) compared with prestudy values. Bleeding frequency decreased in 5 subjects compared with historical rates. These results demonstrate that this retroviral vector (hFVIII(V)) is safe and, in some subjects, persists more than a year in peripheral blood mononuclear cells, with measurable factor VIII levels and with increased available FVIII activity (increased T1/2 and AUC) after infusion of exogenous FVIII concentrate.