Ziprasidone and the pharmacokinetics of a combined oral contraceptive

Abstract

Aims To determine whether multiple doses of ziprasidone alter the steady-state pharmacokinetics of the component steroids, ethinyloestradiol and levonorgestrel, of an oral contraceptive; to evaluate the tolerability of a co-administered combined oral contraceptive and ziprasidone; and to compare plasma concentrations of prolactin in subjects taking a combined oral contraceptive with placebo or ziprasidone. Methods Nineteen women taking a combined oral contraceptive (ethinyloestradiol 30 mg day x 1 and levonorgestrel 150 mg day x 1 ) were enrolled into a double-blind, placebo-controlled, two-way crossover study. They received ziprasidone 40 mg day x 1 in two divided daily doses or placebo for 8 days (days 8±15) in one of two 21 day treatment periods separated by a 7 day washout period. Venous blood samples were collected immediately before and up to 24 h after the morning dose of oral contraceptive and ziprasidone or placebo on day 15 of each 21 day treatment period. These were assayed for ethinyloestradiol and levonorgestrel and the resulting data used to derive pharmacokinetic data for these steroids. Additional samples were collected immediately before and 4 h after the morning dose of oral contraceptive and ziprasidone or placebo on day 15 of each 21 day treatment period for prolactin assay. All observed and volunteered adverse events were recorded throughout the study. Results The mean AUC(0,24 h), C max and t max for ethinyloestradiol and the mean AUC(0,24 h) and C max for levonorgestrel during ziprasidone co-administration were not statistically signi®cantly different from corresponding values occurring during placebo co-administration. The t max for levonorgestrel was approximately 0.5 h longer. Concomitant therapy with a combined oral contraceptive and ziprasidone did not result in adverse events not previously seen with either preparation alone. Conclusions The ®ndings of this study suggest that, based on pharmacokinetic and tolerability data, ziprasidone may be co-administered with ethinyloestradiol and levonorgestrel without loss of contraceptive ef®cacy or increased risk of adverse events.

Ziprasidone, a New Atypical Antipsychotic Drug

“…17 The lack of CYP3A4 inhibition was supported by a lack of an AUC increase following exposure to ethinylestradiol, a CYP3A4 substrate, on coadministration with ziprasidone. 25 The effect of ziprasidone on CYP2D6 activity was assessed by administering ziprasidone 80 mg, placebo, or paroxetine 20 mg (a potent CYP2D6 inhibitor) 2 hours before administering dextromethorphan (a model CYP2D6 substrate). Ziprasidone did not change the urinary ratio of dextromethorphan to dextrophan (dextromethorphan's CYP2D6 primary metabolite) compared with placebo, whereas it was increased 10-fold after paroxetine administration.…”

The effect of carbamazepine on the steady‐state pharmacokinetics of ziprasidone in healthy volunteers

“…Studies performed in vitro using human liver microsomes have shown that the oxidative metabolism of ziprasidone is mediated primarily by CYP3A4 [1]. In vivo studies have demonstrated no clinically significant pharmacokinetic interactions between ziprasidone and cimetidine (which inhibits several isoforms of CYP including CYP3A4), ethinyloestradiol (which is metabolized by CYP3A4), or ketoconazole (a potent inhibitor of CYP3A4), suggesting that co‐administration with other CYP3A4 inhibitors or inducers will not require dose adjustment [2–4].…”

‘Atypical’ antipsychotics: where does ziprasidone fit?

“…Carbamazepine (CBZ), which can induce CYP3A4, led to a modest decrease in steady-state exposure to ziprasidone (36%) that was thought to be clinically insignificant [45]. Coadministration of ziprasidone with a combined oral contraceptive containing ethinyloestradiol, a CYP3A4 substrate, indicated no clinically significant effect on the pharmacokinetics of the oral contraceptive [47]. Coadministration of ziprasidone with a combined oral contraceptive containing ethinyloestradiol, a CYP3A4 substrate, indicated no clinically significant effect on the pharmacokinetics of the oral contraceptive [47].…”