Pharmacokinetics of metrifonate and its metabolite dichlorvos in healthy volunteers and in patients with renal impairment

Objective: 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/1.73m(2); group B - patients with CLCR >60-less than or equal to 90 ml/min/1.73m(2); group C - patients with CLCR >30-less than or equal to 60 ml/min/1.73m(2); and group D - patients not receiving dialysis, with CLCR less than or equal to 30 ml/min/1.73m(2). 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 (C-max) 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.