Pharmacokinetics of oral single-dose clomiphene citrate (CC) in polycystic ovary patient with anovulatory infertility
C. Ghobadi (1, 4), N. Mir-Hosseini (2), M.R. Shiran (3), W.L. Ledger (4), M.S Lennard (1), A. Rostami-Hodjegan (1).
(1) Academic Unit of Clinical Pharmacology, University of Sheffield, UK; (2) Dept. of Pharmacology, Babol Medical University, Babol, Iran; (3) Department of Physiology & Pharmacology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; (4) Academic Unit of Reproductive and Developmental Medicine, University of Sheffield, Sheffeild, UK.
Objectives: Clomiphene citrate (CC) is the first line of treatment for induction of ovulation in anovulatory infertile women with polycystic ovary syndrome (PCOS)1. After over 45 years of therapeutic use the information on pharmacokinetics (PK) of CC is very limited2 and there is no information on PK in PCOS. CC is available as a racemic mixture of two isomers, Zu- and En-CC in the ratio of 38 and 62%, respectively. The primary objective of the present study was to characterize the PK of Zu- and En-CC in patients with PCOS following the oral administration of a single 50 mg CC tablet. Secondary objective was to assess the covariates determining PK.
Methods: Nine patients were recruited after giving informed consent and studies for 21 days from the first day of menstrual cycle. Plasma concentrations of Zu- and En-CC were measured from the second day of the cycle (day 1 of dosing). Noncompartmental analysis was used to determine the PK parameter values and the effects of TBW, ideal body weight (IBW), and %IBW were investigated as potential covariates. Data on concentration-time profiles of CC isomers in healthy individuals were extracted from the only available literature report and PK parameters for both isomers were calculated using these data to compare with values obtained in PCOS patients in this study.
Results: The apparent volume of distribution (Vd/F), oral clearance (CLpo/F) and the half-life (t1/2) were 2.3 ± 0.7×103 L, 22 ± 7 L/h, 129 ± 17 h and 5 ± 4.2×103 L, 723 ± 670, 5±1 for Zu- and En-CC respectively. None of the PK parameters for Zu- or En-CC obtained from PCOS patients in this study were significantly different from those obtained in healthy volunteers. Obesity had statistically significant effects on V/F and CL/F of Zu-CC (p<0.03) but not En-CC.
Conclusions: We have characterized the PK of CC isomers in PCOS anovular patients for the first time. Both isomers appeared to have similar PK to those obtained in healthy individuals. The previous study on PK of CC only focused on the average values and no report was given on the magnitude of inter-individual variability. Current report showed a substantial inter-subject variability in PK parameters. Obesity was investigated as one of the covariates for PK. The distribution and clearance of Zu-CC was different in obese patients and the increase in V/F appeared to be related to TBW indicting an equal increase in the distribution of the drug into adipose and other body tissues. Obesity also increased the absolute value Zu-CC clearance however there was no evidence of change in Zu-CC hepatic biotransformation since the CL/F after correction for TBW was not significantly different between obese and non-obese patients.
References:
[1] Hum Reprod. Jun 1995;10:1549-1553.
[2] Fertil Steril. Sep 1986;46:392-396.
[3] Fertil Steril. May 2004;81:1187-1193.
[4] Curr Opin Endocrinol Diabetes Obes. Dec 2007;14:482-487.
[5] Maturitas. Jul 20 2006;54:363-371.
[6] Arch Gynecol Obstet. Dec 2004;270:205-210.
[7] Clin Pharm. Sep 1987;6:706-714.