Background Pharmacokinetic (PK) parameters based on short sampling times (48 h or less) may contain inaccuracies due to their dependency on extrapolated values. This study was designed to measure PK parameters with greater accuracy in obese users of a low-dose oral contraceptive (OC), and to correlate drug levels with assessments of end-organ activity. Study design Obese (BMI ≥30 kg/m2), ovulatory, otherwise healthy, women (n = 32) received an OC containing 20 mcg ethinyl estradiol (EE)/100 mcg levonorgestrel (LNG) for two cycles. EE and LNG PK parameters were characterized for 168 h at the end of Cycle 1. During Cycle 2, biweekly outpatient visits were performed to assess cervical mucus, monitor ovarian activity with transvaginal ultrasound, and obtain serum samples to measure EE, LNG, estradiol (E2), and progesterone (P) levels. PK parameters were calculated and correlated with end-organ activity and compared against control samples obtained from normal and obese women sampled up to 48 h in a previous study. Standard determination of PK accuracy was performed; defined by the dependency on extrapolated values (‘excess’ area under the curve of 25% or less). Results The mean BMI was 39.4 kg/m2 (SD 6.6) with a range of 30–64 kg/m2. Key LNG PK parameters were as follows: clearance 0.52 L/h (SD 0.24), half-life 65 h (SD 40), AUC 232 h*ng/mL (SD 102) and time to reach steady-state 13.6 days (SD 8.4). The majority of subjects had increased ovarian activity with diameter of follicles ≥8 mm (n = 25) but only seven women had follicles ≥10 mm plus cervical mucus scores ≥5. Evidence of poor end-organ suppression did not correlate with the severity of the alterations in PK. As compared to historical normal and obese controls (48 h PK sampling), clearance, half-life, area under the curve (AUC) and time to reach steady-state were found to be significantly different (p ≤ 0.05) in obese women undergoing a longer duration of PK sampling (168 h). Longer sampling also improved PK accuracy for obese women (excess AUC 20%) as compared to both normal and obese controls undergoing shorter sampling times (48 h) with excess AUCs of 25% and 50%, respectively. Conclusions Obesity results in significant alterations in OC steroid PK parameters but the severity of these alterations did not correlate with end-organ suppression. A longer PK sampling interval (168 h vs. 48 h) improved the accuracy of PK testing.

SUMMARY The dopamine D2 receptors were investigated in vivo in eight neuroleptic-free patients with persistent tardive dyskinesia using positron emission tomography and 76Br-bromospiperone. The striatal receptor density, estimated by the striatum/cerebellum radioligand concentration ratio, was not elevated in patients as compared with age-matched controls but was positively correlated with the severity of orofacial dyskinesia assessed with the Abnormal Involuntary Movement Rating Scale. These results indicate that tardive dyskinesia is associated with normal levels of striatal D2 receptors but the severity of orofacial movements may depend on the relative density of striatal D2 receptors.Tardive dyskinesia (TD) is a protracted, sometimes permanent, complication of long-term neuroleptic treatment, affecting 13% to 31% of treated schizophrenic patients.'2 It is a distressing condition as the involuntary movements affect the orofacial musculature and often do not respond to therapy save for reintroduction or increased dosage of neuroleptics. There is no established preventive measure other than restricting prescription, and limiting both dosage and duration, of neuroleptic treatment as much as possible.3Brain dopamine receptor hypersensitivity is the most widely accepted hypothesis for the development of TD: it resembles levodopa-induced dyskinesia; it is both caused and controlled by dopaminergic antagonists and aggravated by dopaminergic agonists; during and following chronic neuroleptic treatment, rodents show increased behavioural responses to dopaminergic agonists with correlated increase in dopamine D2 receptor density in the striatum.4 Until now, however, no direct evidence for this role of striatal D2 receptors has been obtained in prospectively selected TD patients. We have evaluated striatal D2 receptors in TD patients in vivo using positron emission tomography (PET) and 76Br-bromospiperone to investigate the following hypothesis: (1) the striatal D2 receptors are increased in TD, and (2) the D2 receptor density is correlated to the severity of TD. Eight dyskinetic patients were studied after giving informed consent (table 1). The eight TD patients (7 women and I man, mean age 64-3 years, SD 4 7) were compared with eight agematched controls (3 women and 5 men, mean age 63 5, SD 2 6). The diagnosis of TD was established when abnormal involuntary movements (AIMS) (of a choreic nature), without other neurological abnormalities, had been permanent for the past 3 months, affecting in all cases the oro-linguofacial area and sometimes also the limbs or trunk, and had begun following a minimum of 3 months of exposure to neuroleptics, persisting at least 9 days after withdrawal of the neuroleptics (the type of which not being relevant). Neuroleptics had been prescribed, sometimes for many years, by general practitioners for reasons not always clear, particularly in the six chronically depressed patients. The characteristics ofdyskinesia and the plasma concentration of prolactin (as an index of neuroleptic medicati...

Objective Pharmacokinetics of norethindrone in combination oral contraceptive regimen are well described among HIV+ women treated with ritonavir boosted protease inhibitor therapies; however such characterization is lacking in women using progestin-only contraception. Our objective is to characterize pharmacokinetics of norethindrone in HIV+ women using ritonavir boosted atazanavir treatment during progestin-only contraceptive regimens. Study Design An open-label, prospective, non-randomized trial to characterize the pharmacokinetics of norethindrone in HIV+ women receiving ritonavir boosted atazanavir (n=10;treatment group) and other antiretroviral therapy known to not alter norethindrone levels (n=17;control group) was conducted. Following informed consent, women were instructed to take a single daily fixed oral dose of 0.35 mg norethindrone and 300mg/100mg atazanavir/ritonavir for 22 days. On day 22 serial blood samples were collected by venous catheter at 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours. Whole blood was processed to collect serum and stored at −20°C until later analysis using radioimmunoassay. Pharmacokinetic parameters were estimated using non-compartmental method. Results In the treatment group, compared to the control group, an increase in area under the curve0-24 (16.69hr*ng/mL vs. 25.20hr*ng/mL; p<0.05) and maximum serum concentration (2.09ng/mL vs. 3.19ng/mL; p<0.05), decrease (25-40%) in apparent volume of distribution and apparent clearance, and unaltered half-life were observed. Conclusion(s) Our findings suggest that progestin-only contraceptives, unlike combination oral contraceptives, benefit from drug-drug interaction and achieve higher levels of exposure. Further studies are needed to establish whether pharmacokinetic interaction leads to favorable clinical outcomes.