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 (ACh E) and of butyrylcholinesterase in plasma (BChE) in healthy individuals and in patients with renal impairment. We also assessed the tolerability of me trifonate in these individuals. Design: The study was a nonblinded, nonrandomised, noncontrolled, observati onal investigation in which participants were assigned to one of four group s according to their creatinine clearance (CLCR) values prior to drug admin istration. Metrifonate, in the form of a 50mg tablet, was administered oral ly as a single dose. Study Participants: The study included 24 individuals (15 men and nine wome n 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 - patie nts with CLCR >60-less than or equal to 90 ml/min/1.73m(2); group C - patie nts with CLCR >30-less than or equal to 60 ml/min/1.73m(2); and group D - p atients 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 th e pharmacokinetics of metrifonate. The area under the concentration-time cu rve (AUC) of DDVP was unchanged between groups. Maximum observed blood conc entration (C-max) values of DDVP were slightly lower in patients with moder ate or severe renal impairment than in healthy individuals. Renal impairmen t did not influence the inhibition of BChE at trough. Metrifonate was well tolerated. Diarrhoea in one patient was considered to be possibly drug rela ted. There were no clinically relevant influences of metrifonate on laborat ory parameters, blood pressure, pulse, electrocardiogram, bodyweight or phy sical examination. Conclusion: Renal function did not significantly affect the pharmacokinetic s of metrifonate. This result is in keeping with the finding that renal exc retion of unchanged metrifonate (0.6 to 1.9% of dose within 24 hours) and o f 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 propo rtion to CLCR this single-dose study does not predict any significant accum ulation of either metrifonate or DDVP in a steady-state situation. Adjustme nt of metrifonate dosage is not required in renally impaired patients.