Roland Heinig

Pharmacokinetics of Metrifonate and its Metabolite Dichlorvos in Healthy Volunteers and in Patients with Renal Impairment

AbstractObjective: A clinical-pharmacological study was carried out to evaluate the pharmacokinetics of metrifonate and its active metabolite dichlorvos (DDVP), and the pharmacodynamics of acetylcholinesterase in red blood cells (AChE) and of butyrylcholinesterase in plasma (BChE) in healthy individuals and in patients with renal impairment. We also assessed the tolerability of metrifonate in these individuals. Design: The study was a nonblinded, nonrandomised, noncontrolled, observational investigation in which participants were assigned to one of four groups according to their creatinine clearance (CLcr) values prior to drug administration. Metrifonate, in the form of a 50mg tablet, was administered orally as a single dose. Study Participants: The study included 24 individuals (15 men and nine women aged 45 to 75 years) of whom six were assigned to each group as follows: group A — healthy individuals with CLcr >90 ml/min/1.73m2; group B — patients with CLcr >60−≤90 ml/min/1.73m2; group C — patients with CLcr >30−≤60 ml/min/ 1.73m2; and group D — patients not receiving dialysis, with CLcr ≤30 ml/ min/1.73m2. Groups A to D were comparable in terms of gender, and groups B to D were also of similar age (52 to 63 years). Results: There was no clinically relevant influence of renal function on the pharmacokinetics of metrifonate. The area under the concentration-time curve (AUC) of DDVP was unchanged between groups. Maximum observed blood concentration (Cmax) values of DDVP were slightly lower in patients with moderate or severe renal impairment than in healthy individuals. Renal impairment did not influence the inhibition of BChE at trough. Metrifonate was well tolerated. Diarrhoea in one patient was considered to be possibly drug related. There were no clinically relevant influences of metrifonate on laboratory parameters, blood pressure, pulse, electrocardiogram, bodyweight or physical examination. Conclusion: Renal function did not significantly affect the pharmacokinetics of metrifonate. This result is in keeping with the finding that renal excretion of unchanged metrifonate (0.6 to 1.9% of dose within 24 hours) and of DDVP (<0.1%) is a quantitatively minor pathway in the elimination of the drug. As there is no evidence for changes in elimination half-life in proportion to CLcr, this single-dose study does not predict any significant accumulation of either metrifonate or DDVP in a steady-state situation. Adjustment of metrifonate dosage is not required in renally impaired patients.

Effect of gender and age on the pharmacokinetics of repinotan

AbstractObjective: Repinotan hydrochloride (repinotan) is a selective, high-affinity, full serotonin receptor agonist at the 5-HT1a subtype that is undergoing clinical development in acute stroke. To investigate whether gender is an important covariable for repinotan pharmacokinetics, two studies were performed in subjects of different age and gender who had been phenotyped as extensive metabolisers for cytochrome P450 (CYP)2D6 using dextromethorphan as model substrate. Subjects and methods: Both studies were placebo-controlled, double-blind, randomised, parallel-group studies. Study I was conducted in six healthy young males, five healthy elderly males, and four healthy elderly females receiving a continuous intravenous (IV) infusion of repinotan 0.45 μg/kg/h or placebo for a duration of 12 hours. Study II was performed in healthy elderly male and female volunteers aged ≥65 years with 67 subjects receiving repinotan and 34 receiving placebo. Subjects received a 12-hour infusion of repinotan at doses of 0.1, 0.3, 0.5, 1.0, 2.0 or 3.0 μg/kg/h. Results: Following IV infusion, the steady-state plasma concentration (Css) for repinotan was reached after 4–6 hours consistent with its half-life of 0.8–1.8 hours. In both male and female subjects, the volume of distribution at steady-state and plasma clearance (CL) were independent of dose, indicating linear pharmacokinetics and dose-proportionality for area under the concentration-time curve (AUC) and peak plasma concentration (Cmax) over the dose range of 0.1–3.0 μg/kg/h. Compared with elderly subjects, repinotan CL was unchanged in a subgroup of young subjects. The pooled evaluation of elderly subjects (n = 67) showed that gender had no influence on the pharmacokinetics of repinotan. The ratios male : female and their 90% CIs were: 0.91 (0.789, 1.052) for dose/ bodyweight-normalised Cmax (Cmax, norm), 0.95 (0.808, 1.110) for half-life, 0.97 (0.900, 1.044) for Vss, and 1.11 (0.923, 1.336) for CL. Conclusion: These results indicate that gender does not affect the pharmacokinetics of repinotan in healthy subjects whose age (≥65 years) was representative of the target patient population for repinotan in acute stroke.

Disposition of a Single Dose of Warfarin in Healthy Individuals after Pretreatment with Metrifonate

AbstractObjective: Metrifonate, through its active metabolite dichlorvos, is an acetylcholinesterase inhibitor effective in the treatment of Alzheimer’s disease (AD). Patients with AD often require treatment with warfarin, which has a narrow therapeutic index. In view of the many reported interactions of warfarin, it was essential to ascertain whether the combined administration of metrifonate and warfarin altered the anticoagulant actions of warfarin. This study was therefore designed to determine the effects of pretreatment with multiple doses of metrifonate or placebo on the pharmacokinetic and pharmacodynamic properties of a single dose of warfarin in healthy persons. Design: This was a double-blind, placebo-controlled, two-treatment, two-period, crossover study. The participants received metrifonate 50mg once daily or matching placebo for two periods of 8 days each, separated by a 21-day period. On the morning of the fourth day of each 8-day period, every participant received 25mg of racemic warfarin (5 sX 5mg oral tablets). Study Participants: Fourteen healthy Caucasians (12 men and two women), aged 18 to 45 years, were included. Target Parameters: The effects of pretreatment with metrifonate or placebo on the pharmacokinetic and pharmacodynamic characteristics of warfarin were evaluated, as assessed by plasma concentrations of (R)- and (S)-warfarin, prothrombin time and factor VII activity. The safety and tolerability of both treatments was recorded. Results: The 90% confidence intervals for the true mean ratios of warfarin plus metrifonate to warfarin alone were within the range of 0.80 to 1.25 for the primary test parameters, area under the curve (AUC) of prothrombin time versus time and maximum prothrombin time, as well as for the AUC of plasma concentration versus time and the maximum plasma concentration for both warfarin enantiomers. The two treatments were equivalent with regard to these parameters. The study drugs were generally well tolerated. Conclusion: Pretreatment with a therapeutic dose of metrifonate does not significantly influence the pharmacokinetic or pharmacodynamic characteristics of a single dose of warfarin in healthy volunteers. Based on the similarity in pharmacokinetics of metrifonate in volunteers and patients with AD, this study also predicts the absence of an effect of metrifonate on warfarin in the target population of the drug.

Pharmacokinetics of Escalating Doses of Intravenous Repinotan in Healthy Male Volunteers

AbstractObjective: To investigate the pharmacokinetics of intravenous (IV) repinotan, a potent selective full serotonin (5-HT1a) receptor agonist, after administration of escalating doses/infusion rates to healthy volunteers with extensive or poor metaboliser phenotype, and to compare weight-adjusted (mg/kg) to fixed (mg/ day) dosing regimens. Subjects and methods: The pharmacokinetic profile of IV repinotan was evaluated in healthy male volunteers. In eight studies, extensive metabolisers (EMs) and poor metabolisers (PMs) identified by sparteine phenotyping were given IV repinotan at doses of 5–100μg over 1 hour or 200–1000μg over 4 hours. In two additional studies of EMs and PMs, IV repinotan was administered as a weight-adjusted dose of 1 μg/kg/h for 24 hours. Repinotan plasma concentrations were measured for determination of non-compartmental pharmacokinetic parameters. Results: Sixty-five male subjects (54 EMs and 11 PMs) were valid for pharmacokinetic evaluation. During continuous IV infusion, a steady-state repinotan plasma level was reached within 4–5 hours in EMs, and the elimination half-life was 1 hour. Pharmacokinetics were linear in EMs across a wide range of doses (5–2250μg) and infusion rates (5–250μg/h). Repinotan clearance was correlated with the log metabolic ratio (MR) of sparteine as an indicator for cytochrome P450 (CYP)2D6 phenotype, and subjects phenotyped as PMs had reduced clearance, resulting in longer elimination half-lives (up to a mean value of 11 hours) and increased peak plasma concentrations and area under the concentration-time curve values. Bodyweight was not a significant covariable for clearance and the interindividual variability in clearance was not reduced after normalisation to bodyweight. Repinotan was well tolerated at infusion rates up to 150 μg/h (EMs), and no clinically relevant safety issues were reported. Conclusion: Repinotan demonstrates linear pharmacokinetics in EMs for CYP2D6, who constitute about 93% of the Caucasian population. Repinotan clearance is correlated with CYP2D6 phenotype and reduced in PMs. Bodyweight does not appear to be a major determinant of its pharmacokinetic variability and a bodyweight-adjusted dosing regimen is not warranted. Further studies should be performed in patients to investigate whether the tolerability profile of repinotan is comparable to that observed in healthy volunteers.