Saturable metabolism of perhexiline maleate: Correlations with long-term toxicity

Abstract

VERAPAMIL IN THE TREATMENT OF PRINZMETAL'S VARIANT ANGINA: A LONG-TERM, DOUBLE-BLIND, RANDOMIZED TRIAL. SM Johnson, MD, DR Mauritson, MD, LD Hillis, MD, FACC, JT Willerson, MD, FACC, U of Texas Health Science Center, Dallas, TX. This study was performed to assess the efficacy of verapamil (V) in patients (pts) with variant angina pectoris (VAP). 1n 13 pts (8 men, 5 women, mean age 52 yrs) with VAP, V (38&76 mg/day, meanfSD) was compared to placebo (P) in a double-blind, randomized, double-crossover trial of 9 months duration: 1 month of open-label V followed by four 2-month periods of blinded therapy (V-P-V-P or P-VP-V). Ten of 13 pts were maintained on stable doses of isosorbide dinitrate (128*55 mg/day) throughout the study. During each Z-month period, the following were quantitated: (1)chest pains/week (wk). (2)nitroglycerin (NTG) used/wk, and (3)required hospitalizations (HOS) for clinical instability. During the 4 months of V, the number of chest pains/wk (2.0f3.5) and the number of NTG/wk (2.5* 4.5) were less (pcO.01) than during P (12.1*27.8 pains/wk, 15.7f37.5 NTG/wk). None of 13 required HOS during V, but 4/13 required a total of 5 HOS during P (pcO.05). Of the 13 pts, 6 had clinical activity throughout the study, but the other 7 (54X) had prolonged periods of inactivity which, in 6/7, lasted the entire 8 months. In the 6 active pts V had a marked salutary effect (3.8f3.1 pains/wk, 4.645.7 NTG/wk) h w en compared to P (24.7f36.2 painslwk, 3O.lf49.8 NTG/wk, p<O.Ol). V was well tolerated, causing only minor constipation not requiring a change,of dosage. Thus, (1)many patients with variant angina have prolonged periods of clinical quiescence even without calcium antagonists, emphasizing the need for properly-designed studies of potential therapeutic agents; and (2)in a long-term, double-blind, randomized study, verapamil is safe and efficacious in the treatment of variant angina and is especially beneficial in those with clinically-active disease. SATURABLE HETABOCISH OF PERHEXILINE MALEATE: CORRELATIONS WITH LONG-TERM TOXICITY John D. Horowitz, MB; Pamela M. Morris, BSc; Olaf Drummer, MSc; Alan J. Goble, MD; and William J. Louis, MD, Departments of Cardiology and Clinical Pharmacology,Austin Hospital, Heidelberg, Victoria, Australia. Perhexiline maleate (Px) is a calcium channel antagonist which is an effective prophylactic anti-angina1 a‘gent, with minimal cardiovascular adverse effects. However, the chronic administration of Px may cause hepatitis or peripheral neuropathy, limiting the clinical usefulness of Px, which is cleared largely by hepatic hydroxylation. The current investigation examines the possibility of a pharmacokinetic basis for these adverse effects. Single-dose pharmacokinetic studies were performed in six patients with severe angina pectoris using oral Px doses of 150 and 300 mg. A sensitive (threshold 5 ng/ml) and specific high performance liquid chromatographic assay was used. Doubling of the Px dose was associated with a prolongation of mean elimination half-life (from ll.Zf2.1 S.E.M. to 19.1 k-2.8 hours; p<O.Ol) and a disproportionate increase (mean 5.3-fold)in area under the plasma concentration-time curve suggesting saturable hepatic hydroxylation of Px. Steadystate studies in 17 patients treated with Px indicated a therapeutic plasma concentration range of approximately 150 to 600 ng/ml. Five cases of Px toxicity (2 of peripheral neuropathy, one each of hepatitis, blurred vision and nausea) were all associated with Px levels above 700 ng/ml (mean 15702370 ng/ml), and were reversible with readjustment of Px dosage. We conclude that Px is a longacting calcium channel antagonist which is prone to accumulate in some patients due to limited capacity for hepatic Px metabolism. Monitoring of plasma Px concentrations at regular intervals will permit optimization of long-term therapy with Px. BENEFITS OF ADDED NIFEDIPINE IN UNSTABLE ANGINA PERSISTING DESPITE BETA BLOCKADE AND ISOSORBIDE DINITRATE Frans Hagemeijer, MD, FACC, Sint Franciscus Gasthus and Thoraxcenter, Erasmus University, Rotterdam, The Nether-