Effect of Topiramate on the Pharmacokinetics of an Oral Contraceptive Containing Norethindrone and Ethinyl Estradiol in Patients with Epilepsy

Summary: Purpose: Because enzyme-inducing antiepileptic drugs (AEDs) can affect pharmacokinetics of oral contraceptives and thereby cause contraceptive failure, the potential effect of topiramate, a new AED, on the pharmacokinetics of the combination oral contraceptive norethindrone/ethinyl estradiol was evaluated. Methods: Twelve women receiving stable valproic acid (VPA) monotherapy for epilepsy received a combination norethindrone 1.0 mg/ethinyl estradiol 35-μg tablet daily for 21 days followed by seven daily doses of inert tablets for four 28-day cycles. After a baseline cycle (cycle 1), topiramate 100, 200f and 400 mg every 12 h was administered in cycles 2 through 4, respectively. Serial blood samples were obtained on day 20 of each cycle and were analyzed for norethindrone, ethinyl estradiol, and progesterone by using validated radioimmunoassay methods. Results: Compared with cycle 1, none of the norethindrone pharmacokinetic parameters changed significantly in the presence of topiramate, 100–400 mg every 12 h. Individual patient serum progesterone concentrations measured during each cycle were at or close to the limit of quantification with no apparent differences among cycles. However, mean area under the concentration-versus-time curve over the 24-h period (AUC_0–24) values for ethinyl estradiol were 18–30% lower in cycles 2 through 4 compared with cycle 1 (p 0.05 for all pairs), whereas mean oral serum clearance (CL/F) values were 14.7–33.0% higher (p 0.05 for cycles 2 and 4 vs. cycle 1). Mean time of peak concentration (T_max values determined during topiramate therapy were not significantly different from those at baseline. Conclusions: When prescribing an oral contraceptive for patients receiving topiramate, clinicians should consider initial therapy with an agent containing 235 μg of ethinyl estradiol.     

A Double-Blind, Placebo-Controlled Study on the Effect of Vigabatrin on In Vivo Parameters of Hepatic Microsomal Enzyme Induction and on the Kinetics of Steroid Oral Contraceptives in Healthy Female Volunteers

Summary: Purpose: This study was conducted to determine whether vigabatrin affects in vivo indices of hepatic microsomal enzyme activity and the pharmacokinetics of steroid oral contraceptives in healthy subjects. Methods: Under double-blind conditions, 13 female healthy volunteers received, in random order and with a washout interval of ≤= 4 weeks, two oral 4-week treatments with vigabatrin (VGB) (maintenance dosage, 3,000 mg daily) and placebo, respectively. The clearance and half-life of antipyrine (a broad marker of drug oxidation capacity), the urinary excretion of 6-β-hydroxycortisol (a selective marker of cytochrome CYP3A-mediated oxidation), and the activity of serum γ-glutamyltransferase (a nonspecific index of microsomal enzyme activity) were determined after 3 weeks of each treatment. The single-dose kinetics of a combined oral contraceptive containing 30 μg ethinyl estradiol and 150 μg levonorgestrel were also determined after 3 weeks of treatment by specific radioimmunologic assays. Results: VGB treatment had no influence on antipyrine clearance (28 ± 5.6 vs. 30 ± 4.5 ml/h/kg on placebo), antipyrine half-life (15.5 ± 3.5 vs. 14.1 ± 2.1 h), urinary 6–β-hydroxycortisol excretion (488 ± 164 vs. 470 ± 228 nmol/day), 6-β-hydroxycortisol-to-cortisol concentration ratio (6.8 ± 3.1 vs. 6.1 ± 3.1) and serum γ-glutamyltransferase activity (12 ± 3 vs. 11 ± 3 IUIL). No difference in pharmacokinetic parameters between VGB and placebo sessions were found for ethinyl estradiol (half-life, 12.5 ± 3.2 vs. 13.9 ± 3.2 h; AUC, 874 ± 301 vs. 939 ± 272 ng/L/h) and levonorgestrel (half-life, 17.7 ± 5.2 vs. 23.1 ± 9.8 h; AUC, 27.5 ± 9.6 vs. 30.0 ± 12.0 μg/L/h). Two subjects, however, showed a 50 and a 39% reduction in ethinyl estradiol AUC during VGB treatment. Conclusions: At therapeutic dosages, VGB did not modify in vivo indices of hepatic microsomal enzyme activity and did not interfere significantly with the CYP3A-mediated metabolism of ethinyl estradiol and levonorgestrel. Based on these data, VGB is unlikely to affect consistently the efficacy of steroid oral contraceptives or interact pharmacokinetically with drugs that are eliminated mainly by oxidative pathways, particularly those involving cytochrome CYP3A.     

Effect of topiramate or carbamazepine on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in healthy obese and nonobese female subjects

PURPOSE: To study the pharmacokinetics of a combination oral contraceptive (OC) containing norethindrone and ethinyl estradiol during OC monotherapy, concomitant OC and topiramate (TPM) therapy, and concomitant OC and carbamazepine (CBZ) therapy in order to comparatively evaluate the pharmacokinetic interaction, which may cause contraceptive failure. METHODS: This randomized, open-label, five-group study included two 28-day cycles. Five groups of female subjects received oral doses of ORTHO-NOVUM 1/35 alone (cycle 1) and then concomitant with TPM or CBZ (cycle 2). The treatment groups were group 1, TPM, 50 mg/day; group 2, TPM, 100 mg/day; group 3, TPM, 200 mg/day; group 4, TPM, 200 mg/day (obese women); and group 5, CBZ, 600 mg/day. Group 4 comprised obese women whose body mass index (BMI) was between 30 and 35 kg/m(2). The BMI of the remaining four groups was < or =27 kg/m2. RESULTS: Coadministration of TPM at daily doses of 50, 100, and 200 mg (nonobese) and 200 mg (obese) nonsignificantly (p > 0.05) changed the mean area under the curve (AUC) of ethinyl estradiol by -12%, +5%, -11%, and -9%, respectively, compared with OC monotherapy. A similar nonsignificant difference was observed with the plasma levels and AUC values of norethindrone (p > 0.05). CBZ (600 mg/day) significantly (p < 0.05) decreased the AUC values of norethindrone and ethinyl estradiol by 58% and 42%, respectively, and increased their respective oral clearance by 69% and 127% (p < 0.05). Because CBZ induces CYP 3A-mediated and glucuronide conjugation metabolic pathways, the significant increase in the oral clearance of ethinyl estradiol and norethindrone was anticipated. CONCLUSIONS: TPM, at daily doses of 50-200 mg, does not interact with an OC containing norethindrone and ethinyl estradiol. The lack of the TPM-OC interaction is notable when it is compared with the CBZ-OC interaction.     

Interaction between brivaracetam (100 mg/day) and a combination oral contraceptive: A randomized,double‐blind,placebo‐controlled study

This randomized, double‐blind, placebo‐controlled, two‐way crossover study aimed to assess the pharmacokinetic interactions between brivaracetam 100 mg/day and a combination oral contraceptive (OC) containing 30 μg ethinylestradiol and 150 μg levonorgestrel. The study was performed in 28 healthy women over five 28‐day menstrual cycles: baseline (OC only), two treatment cycles with brivaracetam (50 mg b.i.d.) or placebo coadministered with OC separated by a wash‐out cycle (OC only), and a follow‐up cycle (OC only). The OC was administered on days 1–21 of each cycle, and brivaracetam or placebo on days 1–28 of the treatment cycles. Pharmacokinetics of ethinylestradiol and levonorgestrel were determined on day 20; brivaracetam morning trough levels on days 20 (with OC) and 29 (without OC) were compared. C_max (maximum plasma concentration) and AUC (area under the plasma concentration versus time curve) ratios for brivaracetam versus placebo (90% confidence interval [CI]) were 0.96 (0.88–1.04) and 0.90 (0.86–0.95) for ethinylestradiol, and 0.95 (0.91–0.99) and 0.92 (0.88–0.97) for levonorgestrel, within predefined bioequivalence limits (0.80–1.25). Brivaracetam trough levels were similar on days 20 and 29 (ratio 1.08; 90% CI 0.98–1.18). No differences in breakthrough bleeding were seen across the five cycles. It was concluded that there were no interactions between brivaracetam 100 mg/day and the OC. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

An open study of tolerability and pharmacokinetics of raclopride extended release capsules in psychiatric patients: a Canadian study.

The tolerability and pharmacokinetics of raclopride extended release (ER) capsules have been evaluated after a single oral dose and at steady state, with 3 different daily doses in 4 male patients requiring neuroleptic treatment. In this 3-week open study, the drug was administered to patients in increasing bid doses of 8 mg, 12 mg and 16 mg, respectively, for each 1-week treatment period, following a 1-week placebo washout. With this limited number of patients, assessments of clinical chemistry, hematology, cardiovascular variables and adverse symptoms suggest that raclopride is safe and well-tolerated in the group studied. The administration of repeated doses of raclopride showed linear pharmacokinetics based on parameter values which are either constant (effective elimination half-life, total plasma clearance, and dose-normalized area under the plasma concentration-time curve) or varying proportionally (trough plasma concentration, peak plasma concentration, average plasma concentration and the area under the plasma concentration-time curve for a dosage interval at steady state) with the doses. The linear 1-compartment open model with zero-order absorption was the most appropriate pharmacokinetic model describing the raclopride plasma concentration profile after a single 8 mg dose of raclopride ER capsules. The ER formulation reduced the fluctuation between peak and trough plasma drug concentrations which has been reported before with instant release dosage forms. In this study, the increase of plasma prolactin concentrations above the normal limit was transient and returned to normal levels. Although the plasma prolactin concentration tended to increase with the drug dose, no direct relationship between raclopride dose and prolactin plasma concentrations was found. The correlation of plasma prolactin response with the plasma raclopride concentration showed a low level of hysteresis.     

Modeling and simulation of intravenous levetiracetam pharmacokinetic profiles in children to evaluate dose adaptation rules

PURPOSE: To develop a pharmacokinetic model for intravenous levetiracetam in children, based on adult intravenous data and pediatric oral data. METHODS: Data from two adult Phase-I studies in which levetiracetam was given intravenously were utilized to develop the adult population pharmacokinetic two-compartment intravenous model. After model qualification, combination with an existing pediatric one-compartment oral population pharmacokinetic model enabled simulation of twice-daily intravenous infusions of levetiracetam in children. Median and 90% confidence intervals for C(trough), C(max) (end of infusion) and AUC(tau) were simulated for 2000 children and compared to the values observed in adults. RESULTS: The population pharmacokinetic two-compartment model successfully described intravenous levetiracetam pharmacokinetics in healthy adults. After combination with the oral pediatric population model, steady-state concentrations at the end of 15-, 30- and 60 min b.i.d. levetiracetam intravenous infusions in children were predicted to be 29-41, 17-24 and 6-13% higher than those observed after oral dosing of 30 mg/kg b.i.d. Concentrations returned to the range of oral exposures within 1h after the infusion peak. The combined model predicted that steady-state peak plasma concentrations and AUC(tau) in children receiving 30 mg/kg twice daily as 15 min intravenous infusions were within the range of predicted and observed C(max,ss) and AUC(tau )values of adults receiving 15 min intravenous infusions of 1500 mg levetiracetam. CONCLUSIONS: The simulations suggest that levetiracetam may be administered intravenously in children as 15 min infusions.     

Induction of Ethinylestradiol and Levonorgestrel Metabolism by Oxcarbazepine in Healthy Women

PURPOSE: To evaluate the effect of oxcarbazepine (OCBZ) on the pharmacokinetic profile of steroid oral contraceptives. METHODS: Twenty-two healthy women aged 18-44 years were recruited, and 16 of them completed the study. By using a randomized double-blind crossover design, each woman was studied in two different menstrual cycles, during which placebo or OCBZ (maintenance dosage, 1,200 mg/day) was given in randomized sequence for 26 consecutive days with a washout of at least one cycle in between. A steroid oral contraceptive containing 50 microg ethinylestradiol (EE) and 250 microg levonorgestrel (LN) was taken for the first 21 days of each cycle. Plasma concentrations of EE and LN were measured by gas chromatography-mass spectrometry in samples collected at regular intervals on days 21-23 of each cycle. RESULTS: Compared with placebo, areas under the plasma concentration curves (AUC(0-24h, geometric means) decreased by 47% for both EE (from 1,677 to 886 pg.h/ml; p < 0.01) and LN (from 137 to 73 ng.h/ml; p < 0.01), during OCBZ treatment. Peak plasma EE concentrations decreased from 180 pg/ml during the placebo cycle to 117 pg/ml during the OCBZ cycle (p < 0.01), whereas peak plasma LN concentrations decreased from 10.2 to 7.7 ng/ml (p < 0.01). The half-lives of EE and LN also decreased from 13.6 to 7.9 h (p < 0.01) and from 28.8 to 15.8 h, respectively (p < 0.01). CONCLUSIONS: OCBZ reduces plasma concentrations of the estrogen and progestagen components of steroid oral contraceptives, presumably by stimulating their CYP3A-mediated metabolism in the liver or gastrointestinal tract or both. Because this may lead to a decreased efficacy of the contraceptive pill, women treated with OCBZ should receive preferentially a high-dosage contraceptive and should be monitored for signs of reduced hormonal cover.     

Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo-controlled trial

PURPOSE: This study evaluates the effect of oral contraceptives on lamotrigine (LTG) plasma concentrations and urine excretion of LTG metabolites in a double-blind, placebo-controlled, crossover study in patients with epilepsy. METHODS: Women with epilepsy, treated with LTG in monotherapy and taking combination-type oral contraceptives, were randomized to treatment with placebo or a standard combination-type contraceptive pill. The dose-corrected trough plasma concentration of LTG and the ratio of N-2-glucuronide/unchanged LTG on urine after 21 days of concomitant placebo treatment was analyzed versus those after 21 days of concomitant treatment with the oral contraceptive pill. RESULTS: The mean dose-corrected LTG concentration after placebo treatment was 84%[95% confidence interval (CI), 45-134%] higher than after oral contraceptives, signifying an almost doubling of the concentration after cessation of oral contraceptives. Most of this increase took place within the first week after oral contraceptives were stopped. The N-2-glucuronide/LTG ratio in the urine was decreased by 31% (95% CI, -20-61%) when shifting from oral contraceptives to placebo. CONCLUSIONS: Cessation of oral contraceptives leads to an 84% increase in the concentration of LTG. In parallel, the excretion of the N-2-glucuronide was decreased, indicating that the changes are caused by altered LTG glucuronidation. The change in LTG concentrations was observed within 1 week of the shift of treatment, suggesting that induction and deinduction of LTG glucuronidation is faster than that seen for other metabolic pathways (e.g., cytochrome P450).     

The participation of histaminergic receptors of the rostral hypothalamus on the tonic release of luteinizing hormone (LH) in adult spayed rats under estrogen and progesterone treatment

Summary The influence of histaminergic sites in the preoptic-anterior hypothalamic area (POA-AHA) on the basal release of luteinizing hormone (LH) under a continuous regimen of estradiol, progesterone, or both was studied in ovariectomized rats. Different groups of animals were subjected to the following experimental schedule: at day 1, rats received a s.c. silastic implant filled with oil, estradiol, progesterone, or estradiol plus progesterone. Seven days later (day 7), animals were implanted into the POA-AHA with microinjection cannulae. At day 8 and 9, the different groups of rats were microinjected with 1 l of saline solution containing 35 nMol of pyrilamine or metiamide, or 20 nMol of alpha-fluoro-methyl-histidine. At day 10, blood samples were taken through a permanent jugular cannulae implanted in situ the day before. LH concentrations were determined in plasma by RIA. Results showed that the increase of LH plasma levels induced by the ovariectomy was inhibited by the estrogen implant, as expected. Treatment of metiamide or alpha-fluoro-methyl-histidine did not affect the pattern of LH secretion. Nevertheless, treatment of metiamide induced a transient increase in the gonadotropin concentrations that extended for two hours (16:00 and 17:00 H). No change in LH plasma levels was observed in rats bearing the progesterone implant. Treatments (pyrilamine, metiamide, or alpha-fluoro-methyl-histidine into the POA-AHA) had no effect. The transient increase in the hormone levels observed in rats treated with pyrilamine in the estrogen-implanted rats was absent in rats bearing the estrogen-progesterone implant. Present data support the concept that histamine is involved in the POA-AHA to control the pituitary LH release and emphasize the role of plasma estrogen to facilitate the expression of HA receptors.     

Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone

OBJECTIVE: To compare severity of negative mood and physical symptoms between women with different progesterone, allopregnanolone, and pregnanolone plasma concentrations during sequential Hormone Replacement Therapy (HRT) with vaginal progesterone suppositories. DESIGN: A randomized, placebo-controlled, double-blind, crossover study. METHOD: Postmenopausal women (n=36) with climacteric symptoms were treated with 2mg estradiol daily during three 28-day cycles. Vaginal progesterone suppositories with 400, 800 mg/day or placebo were added sequentially for 14 days per cycle. Daily symptom ratings using a validated rating scale were kept. Blood samples for progesterone, allopregnanolone, and pregnanolone radioimmunoassays were collected during each treatment cycle. RESULTS: Women were divided into three groups (low, medium, and high) based on plasma allopregnanolone concentration during progesterone treatment. The concentration of allopregnanolone in the medium group corresponds to the concentration seen during the mid luteal phase of the menstrual cycle. Within women with medium allopregnanolone concentration significantly more negative mood and physical symptoms were rated during progesterone treatment compared to treatment with unopposed estrogen or placebo. Between women significantly more negative mood symptoms were seen during progesterone treatment cycles with medium allopregnanolone concentration compared to cycles with low concentration. Plasma progesterone, allopregnanolone, and pregnanolone concentrations increased with increasing progesterone dose. Progesterone and allopregnanolone plasma concentrations increased 2h after vaginal administration of progesterone at 400 and 800 mg/day. CONCLUSION: Vaginal progesterone in sequential HRT causes negative mood, most likely mediated via allopregnanolone.     

Prospective assessment of levetiracetam pharmacokinetics during dose escalation in 4- to 12-year-old children with partial-onset seizures on concomitant carbamazepine or valproate

PURPOSE: To assess the multiple-dose pharmacokinetics of levetiracetam and its major metabolite ucb L057 in children with partial-onset seizures and determine whether it is affected by adjunctive carbamazepine or valproate. To correlate levetiracetam concentrations in plasma and saliva and to assess its safety and clinical response. METHODS: Design was an open-label, multicenter study. Twenty-one children (4-12 years old) with epilepsy taking carbamazepine (13) or valproate (8) received adjunctive levetiracetam. Levetiracetam was initiated at 20 mg/(kg day) and titrated at 2-week intervals to 40 and then 60 mg/(kg day). Twelve-hour pharmacokinetics were determined at the end of each 2-week period. Efficacy was estimated from the partial seizure frequency per week and Global Evaluation Scale. RESULTS: Levetiracetam was rapidly absorbed following oral dosing, with median t(max) of 0.5 h. Dose proportional increases were observed for C(max) and AUC((0-12)) over the dose range; t(1/2) was 4.9 h. Pharmacokinetics of levetiracetam and ucb L057 were not markedly different with concomitant carbamazepine or valproate; clearance was only 7-13% faster and AUC was decreased by only 15-24% in those on carbamazepine compared to valproate. Levetiracetam did not affect trough carbamazepine or valproate. Concentration in saliva and plasma were strongly correlated. Seizure frequency declined by 50% or more in 43% of subjects in the intent-to-treat population (n=21) and in 56% of those with seizures at baseline (n=16). Marked or moderate improvement occurred in 80% and 75% of patients based on Global Evaluation Scale ratings by investigators and parents/guardians, respectively. Levetiracetam was well tolerated. CONCLUSION: Levetiracetam exhibits simple pharmacokinetics in children, with rapid absorption and dose-proportional kinetics. Small but not clinically relevant differences were observed between subjects receiving carbamazepine and valproate, suggesting significant dose adjustment is usually not necessary. This substantiates prior assessments that levetiracetam clearance is higher in children than adults, necessitating a higher dose in children on a mg/kg basis, and suggests it is useful add-on therapy for children with partial-onset seizures regardless of baseline therapy.     

Lack of effect of repeated administration of levetiracetam on the pharmacodynamic and pharmacokinetic profiles of warfarin.

The objective of this study was to determine if repeated administration of levetiracetam alters the pharmacokinetics or the pharmacodynamics of warfarin. Forty-two healthy subjects (18-50 years old) were recruited into the study. After a dose-finding phase and a stabilization phase, during which a warfarin treatment was introduced and the dose maintained stable for at least 5 days, 18 male and 8 female subjects were eligible and enrolled. Subjects received warfarin (2.5, 5 or 7.5 mg/day) plus levetiracetam 1000 mg bid, and warfarin plus placebo. The treatment periods were 7 days long and were separated by a 3-day wash-out period. The protein binding and the pharmacokinetic profiles of R- and S-warfarin were assessed at steady state by analysis of blood samples, and the anticoagulant effect was measured using the international normalized ratio (INR). The ratios of the geometric means for AUC(ss) (90% confidence interval) between coadministration of warfarin with levetiracetam or with placebo were 97.17% (92.85%, 101.68%) for R-warfarin and 100.16% (96.43%, 104.02%) for S-warfarin. Results for C(max), C(min) and oral clearance were consistent with those of AUC(ss). In addition, the protein binding of warfarin was not affected by the concomitant treatment. The INR values measured the last 5 days of each period were not statistically altered by the concomitant administration of levetiracetam or placebo: 1.59+/-0.18 for warfarin alone, 1.49+/-0.21 when coadministered with placebo, and 1.55+/-0.23 with levetiracetam (means+/-S.D.). The frequency and profile of adverse events under the concomitant therapy of warfarin and levetiracetam were expected for subjects receiving these drugs, and the coadministration was safe. Moreover, levetiracetam pharmacokinetics after repeated warfarin administration did not differ from those previously reported in healthy volunteers. At the doses administered, there is no evidence of a pharmacokinetic or pharmacodynamic interaction between warfarin and levetiracetam.     

Carbamazepine coadministration with an oral contraceptive: effects on steroid pharmacokinetics, ovulation, and bleeding

Purpose: Antiepileptic drugs (AEDs) are widely used in reproductive‐age women. The AED carbamazepine (CBZ) induces the hepatic cytochrome P450 system, thereby accelerating hormone metabolism. We sought to assess the pharmacodynamic effects of CBZ on breakthrough bleeding and ovulation during oral contraceptive (OC) use. Methods: A double‐blind, randomized, crossover study of healthy women ages 18–35 years. Participants took an OC containing 20 μg ethinyl estradiol (EE) and 100 μg levonorgestrel (LNG) for 4 months. Concurrently, participants took 600 mg CBZ or a matching placebo for 2 months each, administered in random order. During the second month of CBZ or placebo, we measured EE and LNG levels 12 times over 24 h, ovarian follicular diameters with eight biweekly vaginal ultrasounds, weekly progesterone levels, and bleeding (using a diary). Key Findings: We enrolled 25 women; 10 completed the study. Five women discontinued because of reversible CBZ side effects. Mean area under the curve (AUC) measurements were lower during CBZ use compared to placebo for EE (1,778 vs. 986 pg*h/ml, p < 0.001) and LNG (24.8 vs. 13.8 pg*h/ml, p = 0.04). Ovulation occurred in 5 of 10 CBZ cycles compared to 1 of 10 placebo cycles (p = 0.06). Three or more days of breakthrough bleeding occurred during 8 of the 10 CBZ cycles compared to 2 of the 10 placebo cycles (p = 0.07). Significance: A commonly used dose of CBZ decreased levels of contraceptive steroids, increased breakthrough bleeding, and permitted ovulation during use of a low‐dose OC. Women treated with CBZ are not adequately protected from pregnancy by low‐dose OCs.     

Effects of the contraceptive patch, the vaginal ring and an oral contraceptive on APC resistance and SHBG: a cross-over study

INTRODUCTION: The transdermal patch (20 microg ethinylestradiol+150 microg norelgestromin daily) and the vaginal ring (15 microg ethinylestradiol+120 microg etonogestrel daily) are new contraceptives, designed to deliver a low dose of hormones, suggesting a low exposure. However, few data are available about their risk of venous thrombosis. The objective was to investigate the effect of the patch, the ring, and an oral contraceptive (30 microg ethinylestradiol+150 microg levonorgestrel daily) on activated protein C sensitivity ratio (APC-sr) and on sex hormone-binding globulin (SHBG) levels in plasma. MATERIALS AND METHODS: After a two month wash-out, 13 volunteers were randomly assigned to either the patch followed by the oral contraceptive or vice versa, or the ring followed by the oral contraceptive or vice versa. All treatments lasted two cycles and were separated by a wash-out of two cycles. APC-sr and SHBG levels were determined on day 18-21 of the second cycle of the wash-out and of each treatment period. RESULTS: Compared to the oral contraceptive, both the patch and the ring led to higher APC resistance (mean difference APC-sr 1.1; 95% CI 0.67-1.52 and 0.55; 95% CI 0.11-1.00, respectively) and higher SHBG levels (mean difference 210 nmol/l; 95% CI 134-286 and 148 nmol/l; 95% CI 48-248, respectively). CONCLUSION: The activity of the protein C system in plasma was impaired more by contraceptive patch and vaginal ring than by an oral contraceptive containing the second generation progestagen levonorgestrel.     

Circulating hormones, EEG, and performance in psychological tests of women with and without oral contraceptives

A comparative study was conducted to examine the interrealtionships between changes in circulating hormomes and the EEG and the performance in psychological tests both of women with normal menstrual cycles and of women using oral contraceptives. EEG and psychological data are analyzed in detail. Blood samples were taken at 2-day intervals for 16 women on normal menstrual cycles and for 16 women on pills. The hormonal results confirmed previous studies. Only the alpha-rhythm of the EEG was slightly but significantly accelerated during the luteal phase of the menstrual cycle, as a result of the influence of progesterone. Oral contraceptive tend to slow the alph-rhythm. In performance tests for reaction time and mathematical ability, scores were better during the luteal phase when increased estradiol and progesterone levels occur but not as good during the immediate preovulatory phase when only estradiol levels are high. The groups using oral contraceptive reacted significantly slower during the luteal phase. This result indicates that 1 or more of the ingredients of combined oral contraceptives may interfere with mental abilities. It is concluded that there is a definite relationship between the alpha-rhythm of the EEG, performance time and quality, and reaction time and between these factors and the levels of progesterone whichchange during the menstrual cycles.     

Antiovulatory Doses of Antagonists of LH-RH Inhibit LH and Progesterone but not FSH and Estradiol Release

The differential regulation of immunoactive FSH and LH secretion by endogenous LH-RH was studied using LH-RH antagonists (Ac-D-Trp^1,2, D-Cpa², D-Lys⁶, D-Ala¹⁰LH-RH (MI-1544) and (Ac-D-Nal¹, D-Phe(pCI²), D-Trp³, D-Cit⁶, D-Ala¹⁰LH-RH (SB-030) in ovariecto-mized (OVX) and regularly cycling rats. Single injections of 10 μg and 100 μg doses and long-term treatment with 10 μg doses of MI-1544 were used in OVX animals. Serum and pituitary LH and FSH, as well as serum estradiol and progesterone was determined by RIA during and/or after the treatment. Single injections of MI-1544 in OVX animals caused prompt (in 2 h) and long-lasting (for more than 24 h) suppression of the serum LH, while no or late decrease (after more than 6 h) of the serum FSH. Long-term treatment with the same analog decreased the serum LH (by 50%) and moderately increased the pituitary LH (by 21%) but did not change the serum and the pituitary FSH concentrations. In normal rats, long-term treatment with both of our analogs also resulted in divergent alterations in the LH and FSH concentrations. Serum LH dropped to undetectable levels, while serum FSH did not change significantly. Pituitary LH increased (by 31 to 41%), while FSH decreased (by 27 to 38%). Marked depression was found in the serum progesterone (by 64%) but no significant change in the serum estradiol levels, after the long-term treatment for 21 days. The ovarian cycles were interrupted, and no ovulation appeared during the treatment. Significant decrease was detectable in the weight of the ovaries (by 46%), whereas the weight of the uteri did not change or slightly elevated (by 22%), after the treatment with SB-030 or MI-1544, respectively. The clear antagonistic effect of the analogs on the LH-RH-stimulated LH and FSH release was tested in the in vitro superfused rat pituitary cell system. In this system our analogs provented both the LH-and the FSH-releasing effect of the LH-RH. The inhibitory effect was longer-lasting on the FSH than on the LH release. Our studies give evidences that the long-term treatment with antiovulatory doses of LH-RH antagonists suppress the LH and progesterone but not the FSH and estradiol secretion and indirectly support the earlier publications suggesting the presence of FSH-releasing factor(s) in the CNS.     

Possible Interaction Between Oxcarbazepine and an Oral Contraceptive

The effect of oxcarbazepine (OCBZ) on the kinetics of an oral contraceptive containing ethinyloestradiol (EE) and levonorgestrel (LNG) was investigated in 13 healthy female volunteers who had previously received the contraceptive for at least 3 months. After 15 days of the first study cycle, each subject received, in addition to the oral contraceptive, 300 mg OCBZ on day 16, 300 mg twice daily on day 17, and 300 mg three times daily from day 18 of the first cycle to day 18 of the next menstrual cycle. The area under the curve values for both EE and LNG decreased when OCBZ was given with the oral contraceptive (p = 0.006, analysis of variance). The results indicate that OCBZ, like most antiepileptic drugs (AEDs), decreases the bioavailability of EE and LNG, perhaps by affecting metabolism or protein binding.     

Effects of sex steroids on brain beta-endorphin

Brain β-endorphin was measured by radioimmunoassay in female rats during different stages of the estrous cycle, during pregnancy, 3 weeks after ovariectomy, and 3 weeks after ovariectomy plus estradiol or estradiol and progesterone replacement. No change in hypothalamic β-endorphin content was noted on the afternoon of diestrus, proestrus, or estrus. However, in 9 rats studied between days 8–20 of pregnancy the mean hypothalamic β-endorphin concentration of41.6 ± 2.24ng/mg protein was significantly higher than the concentration of32.7 ± 1.01 in 21 non-pregnant animals (P < 0.001). Although hypothalamic β-endorphin content did not change 3 weeks after ovariectomy, when ovariectomized rats were treated iwth silastic estradiol capsules for 3 weeks, hypothalami β-endorphin decreased significantly from25.5 ± 1.2to18.3 ± 1.3and15.5 ± 0.94ng/mg protein after low and high dose estradiol treatment respectively (P < 0.001). In a second experiment hypothalamic β-endorphin in ovariectomized rats decreased from27.1 ± 1.5to20.7 ± 1.9ng/mg protein after 3 weeks of estradiol treatment (P < 0.02); the β-endorphin content of the thalamus and midbrain also decreased from8.95 ± 1.5and4.11 ± 0.70to5.24 ± 0.39and2.42 ± 0.25ng/mg protein, respectively (P < 0.025). When progesterone was administered together with estradiol, the decrease in β-endorphin induced in the hypothalamus, thalamus and midbrain by estradiol treatment was partially blocked and β-endorphin concentrations in the latter two regions were no longer significantly different from controls.We conclude that physiologic concentrations of estradiol and progesterone can alter the content of brain β-endorphin and suggest that ovarian steroids may be important regulators of this brain peptide.     

Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement

Rivaroxaban (Xarelto((R))) is an oral, direct factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. The aim was to compare the population pharmacokinetics (PK) and pharmacodynamics (PD) of twice-daily (bid) and once-daily (od) rivaroxaban in patients undergoing total hip replacement (THR). Blood samples were collected from patients enrolled in two phase IIb, dose-ranging studies undertaken to investigate rivaroxaban for thromboprophylaxis after THR. A sparse sampling technique was used and the samples were pooled for PK and PD analysis, which used non-linear mixed effect modelling. Rivaroxaban PK (samples from 758 patients) were well described by an oral, one-compartment model; age and renal function influenced clearance, and body surface area affected volume of distribution. When comparing the same total daily doses, maximum plasma concentrations of rivaroxaban were higher and minimum plasma concentrations were lower with od dosing, compared with bid dosing; however, the 90% intervals overlapped. The area under the plasma concentration-time curve was 18-30% higher in the od than in the bid study. Prothrombin time in seconds (samples from 1181 patients) correlated with rivaroxaban plasma concentrations in a linear fashion in both studies. In conclusion, the PK and PD of rivaroxaban were predictable when given either bid or od. These findings, along with the suggested efficacy and safety of rivaroxaban in the phase II studies, relative to enoxaparin, supported the selection of a convenient, once-daily 10 mg rivaroxaban dose for investigation in phase III studies.     

Initial Human Experience with Ganaxolone, a Neuroactive Steroid with Antiepileptic Activity

Summary: Purpose: Studies were conducted to establish the safety, tolerability, and pharmacokinetics of the antiepileptic drug (AED) ganaxolone. Ganaxolone belongs to a novel class of neuroactive steroids called epalons, which specifically modulate the γ-aminobutyric acid type A (GABA_A) receptor in the central nervous system (CNS). Chemically related to progesterone but devoid of any hormonal activity, the epalons have potent antiepileptic, anxiolytic, sedative, and hypnotic activities in animals.
Methods : Ninety-six healthy male and female volunteers received ganaxolone in a variety of formulations, doses, and dosing regimens. The pharmacokinetics of ganaxolone were systematically characterized, and adverse events associated with drug use were documented.
Results : Ganaxolone was well tolerated after single doses (≥1,500 mg) and after multiple doses (≥300 mg b.i.d for 10 days). Steady-state plasma levels (trough) occurred after ˜7 days of dosing, with mean steady-state plasma concentrations (C_max) in multiple dose studies of between 32 ng/ml (50-mg doses) and 376 ng/ml (500-mg doses). No serious or lifethreatening adverse events attributed to the drug were observed. The majority of adverse events reported were mild (82%) to moderate (14%) and were limited to headache, dizziness, somnolence, gastrointestinal disturbances, and malaise.
Conclusions : Ganaxolone alone or formulated with pharmaceutical-grade excipients is rapidly absorbed from the gastrointestinal tract after oral administration in doses ranging from 50 to 1,500 mg. Pharmacokinetic analysis revealed a linear and proportional increase in the area under the curve (AUC) and C_max values with increasing dose within the expected therapeutic dose range. Safety and tolerability in the clinical program were unremarkable.