First-in-human study to assess the safety, pharmacokinetics and pharmacodynamics of BMS-962212, a direct, reversible, small molecule factor XIa inhibitor in non-Japanese and Japanese healthy subjects.

AIMS: The aims of the present study were to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-962212, a first-in-class factor XIa inhibitor, in Japanese and non-Japanese healthy subjects. METHODS: This was a randomized, placebo-controlled, double-blind, sequential, ascending-dose study of 2-h (part A) and 5-day (part B) intravenous (IV) infusions of BMS-962212. Part A used four doses (1.5, 4, 10 and 25 mg h-1 ) of BMS-962212 or placebo in a 6:2 ratio per dose. Part B used four doses (1, 3, 9 and 20 mg h-1 ) enrolling Japanese (n = 4 active, n = 1 placebo) and non-Japanese (n = 4 active, n = 1 placebo) subjects per dose. The PK, PD, safety and tolerability were assessed throughout the study. RESULTS: BMS-962212 was well tolerated; there were no signs of bleeding, and adverse events were mild. In parts A and B, BMS-962212 demonstrated dose proportionality. The mean half-life in parts A and B ranged from 2.04 to 4.94 h and 6.22 to 8.65 h, respectively. Exposure-dependent changes were observed in the PD parameters, activated partial thromboplastin time (aPTT) and factor XI clotting activity (FXI:C). The maximum mean aPTT and FXI:C change from baseline at 20 mg h-1 in part B was 92% and 90%, respectively. No difference was observed in weight-corrected steady-state concentrations, aPTT or FXI:C between Japanese and non-Japanese subjects (P > 0.05). CONCLUSION: BMS-962212 has tolerability, PK and PD properties suitable for investigational use as an acute antithrombotic agent in Japanese or non-Japanese subjects.

The effect of efavirenz on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy HIV-negative women.

BACKGROUND: Women of childbearing age represent a growing proportion of people living with HIV. Preventing pregnancy is important in HIV-infected women receiving efavirenz as part of their antiretroviral therapy. METHODS: The effects of coadministration of efavirenz (600 mg once daily) on the pharmacokinetics (PK) of the active components (ethinyl estradiol [EE] and 17-deacetyl norgestimate [NGMN]) of Ortho Cyclen(®) (Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ, USA) were investigated in 28 healthy HIV-negative women. The peak plasma concentration (C(max)), area under the concentration-time curve for a dosing interval (AUC([τ])), and lowest plasma concentration (C(min)) for EE and NGMN during cycles of treatment with Ortho Cyclen with and without coadministration of efavirenz were compared. Additionally, a post hoc exploratory analysis was conducted to assess the effect of efavirenz on the PK of an additional progestin, levonorgestrel (LNG). RESULTS: Exposures to EE were similar during coadministration of efavirenz and Ortho Cyclen to those during administration of Ortho Cyclen alone. Exposures to NGMN were substantially decreased following coadministration of efavirenz and Ortho Cyclen (adjusted geometric means for C(max), AUC([τ]) and C(min) decreased by 46%, 64% and 82%, respectively) compared with Ortho Cyclen alone. Consistent with NGMN, LNG exposures were decreased 80-86% by efavirenz. CONCLUSIONS: Although efavirenz had no significant effect on the PK of EE, exposures to the progestin components of Ortho Cyclen, NGMN and LNG, were substantially reduced. The results reinforce the need to use reliable methods of barrier contraception, even when taking oral contraceptives and efavirenz.

The effect of atazanavir/ritonavir on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy women.

BACKGROUND: Coadministration of oral contraceptives with protease inhibitors is complicated by drug interactions. An open-label three-period single-sequence study assessed the effect of coadministration of atazanavir (ATV)/ritonavir (RTV) with Ortho Tri-Cyclen(®) and with Ortho Tri-Cyclen(®) LO (Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ, USA) on the pharmacokinetics (PK) of ethinyl estradiol (EE), norgestimate (NGM), ATV and RTV. METHODS: A total of 20 healthy women aged 18-45 years received study treatments. In the lead-in period and in period 1, participants received a full cycle of Ortho Tri-Cyclen (EE 35 µg with NGM 0.18/0.215/0.25 mg) from days 1-28. In period 2, participants received a full cycle of Ortho Tri-Cyclen LO (EE 25 µg with NGM 0.18/0.215/0.25 mg) plus ATV/RTV (300/100 mg once daily) on days 29-42. PK assessments were performed on days 14 and 42 in periods 1 and 2, respectively. RESULTS: ATV/RTV with dose-normalized EE/NGM resulted in geometric mean reductions of 16% in EE peak plasma concentration (C(max)), 19% in EE area under the concentration-time curve for a dosing interval (AUC([τ])) and 37% in EE lowest plasma concentration (C(min)), compared with EE 35 µg with NGM in the absence of ATV/RTV. NGM with EE and ATV/RTV 300/100 mg once daily resulted in increases of approximately 68%, 85% and 102% in 17-deacetyl NGM C(max), AUC((τ)) and C(min), respectively. Two participants discontinued the study because of adverse events. CONCLUSIONS: ATV/RTV with Ortho Tri-Cyclen was well-tolerated and reductions in EE were not predicted to decrease contraceptive efficacy if the formulation contained ≥30 µg of EE.

Delayed onset of oculogyric crisis and torticollis with intramuscular haloperidol.

OBJECTIVE: To report a case of delayed-onset dystonic reactions, oculogyric crisis (OGC), and torticollis after treatment with intramuscular haloperidol lactate injection. CASE SUMMARY: A 22-year-old Mexican American woman received intramuscular haloperidol lactate 7.5 mg followed 4 hours later by 10 mg. Twenty-six hours after the first injection, the patient reported that she was unable to lower her gaze and that her neck was stiff. She was immediately given intramuscular benztropine 2 mg; there was a nearly complete remission of symptoms within 15 minutes of treatment. An objective causality assessment revealed a probable relationship between the OGC/torticollis and haloperidol therapy. DISCUSSION: Dystonic reactions have been reported in 10-60% of patients treated with neuroleptic medication, most commonly when patients just start or increase the dose of the drug. The highest frequency of dystonic reactions has occurred in patients receiving high-potency neuroleptics. It has also been suggested that haloperidol-induced dystonic reactions are a result of the toxic metabolites of that agent. CONCLUSIONS: OGC and torticollis reactions may occur 12-24 hours after treatment with a high-potency neuroleptic, even in the absence of symptoms of extrapyramidal side effects (EPSEs). The delayed dystonic reaction may begin suddenly (no early EPSE symptomatology).