Pharmacokinetics of Pipamperone from Three Different Tablet Formulations

Abstract

Twenty-four (24) Caucasian male subjects completed a single-blind, randomised, three-treatment, three-period, cross-over study. In each treatment phase, subjects received a single dose of 144 mg pipamperone dihydrochloride (CAS 2448-68-2) (equivalent to 120 mg pipamperone; CAS 1893-33-0) as either the reference product (3 x 40 mg tablets), test product A (3 x 40 mg tablets) or test product B (1 x 120 mg tablet). Each consecutive dosing was separated by a washout period of 14 days. Following each dosing, venous blood samples were collected over a period of 120 h for the determination of plasma pipamperone concentrations by high-performance liquid chromatography. The most common drug related adverse events, ranging from mild to moderate in intensity, were bloodshot eyes, nasal congestion, dry mouth, hypotension and dizziness. The geometric mean Cmax of pipamperone for both the reference product and test product A was 266 ng/ml and for test product B 263 ng/ml. The geometric mean AUC0-infinity was 3107 ng.h/ml for the reference product, 3229 ng.h/ml for test product A and 3108 ng.h/ml for test product B. The two test products were shown to be bioequivalent to the reference product with respect to all pharmacokinetic variables investigated.

Therapeutic Drug Monitoring of Common Antipsychotics

“…Peak plasma concentrations are achieved after 4-12 hours. 228 Recently, a low dose of pipamperone was found to induce the antidepressant effect of the SSRI citalopram, with minimal risk for side effects. Concomitant use of CYP3A4 and CYP2D6 inhibitors are contraindicated.…”

“…45 Because use of pimozide implicates a high risk for cardiotoxic and neurological side effects, dosing in patients has to be performed carefully. 228 Extensive metabolism via oxidative N-dealkylation, piperidine ring hydroxylation, N-oxidation, and amide hydrolysis to inactive metabolites with excretion in urine is seen. 219,220 Depending on the indication, pimozide can be administered in daily doses from 1 to 16 mg, with a mean of 6 mg and a maximum daily dose of 20 mg. 221 The AGNP-TDM guidelines recommend a therapeutic range of 15-20 ng/mL; however, this range is based on a study performed on 11 adults and 7 children with Tourette syndrome.…”

“…TDM would be valuable, however, a clear quantitative relationship between plasma concentrations, efficacy, or adverse reactions are not yet described. 228,230 According to the product information sheet, inducers of CYP isoenzymes like carbamazepine and phenytoin can increase the metabolizing process of pipamperone, requiring dose adjustment. 49,222 Schulz and Schmoldt 223 suggests a range of 4-10 ng/mL without referring to literature and other articles suggest plasma concentrations of 1-15 ng/mL, which is also based on the results of a study on only 9 men with chronic schizophrenia.…”

“…219,220 Depending on the indication, pimozide can be administered in daily doses from 1 to 16 mg, with a mean of 6 mg and a maximum daily dose of 20 mg. 221 The AGNP-TDM guidelines recommend a therapeutic range of 15-20 ng/mL; however, this range is based on a study performed on 11 adults and 7 children with Tourette syndrome. 228 The recommended therapeutic range is 100-400 ng/mL. 219,224 Because of the broad range of indications for pimozide and the rather small patient groups studied in the referred literature, the currently defined plasma concentration ranges are highly variable.…”

Pipamperone Population Pharmacokinetics Related to Effectiveness and Side Effects in Children and Adolescents

“…While data on the efficacy and side effects are scarce, publicly available pharmacokinetic data of pipamperone in children and adolescents are completely missing. In adults, some pharmacokinetic studies have been performed, showing a maximum plasma concentration after 1-2 h and an elimination half-life of 12-30 h [4,21,22]. However, in children and adolescents, both pharmacokinetics and pharmacodynamics are expected to be considerably different, as some consensus based-dosing guidelines advise lowering the starting dose in this population by 95% compared to recommended doses in adults, resulting in 2 mg instead of 40 mg [16].…”