Clarification of contraceptive drug pharmacokinetics in obesity.
Ontology highlight
ABSTRACT:
SUBMITTER: Jusko WJ
PROVIDER: S-EPMC5422994 | biostudies-other | 2017 Jan
REPOSITORIES: biostudies-other
Publications
Clarification of contraceptive drug pharmacokinetics in obesity.
Contraception 20160816 1
Related to concerns about the role of obesity in the efficacy of contraceptive drugs, a review of the literature was carried out in regard to the pharmacokinetics of ethinyl estradiol and various progestins given by various routes of administration. Most studies show that obese women exhibit modestly lower plasma concentrations of these drugs (circa 30%) when given the same doses as normal-weight women. While the mechanism is uncertain, precedence in the literature suggests that this is due to b ...[more]
Similar Datasets
Project description:ImportanceObesity affects nearly one-sixth of US children and results in alterations to body composition and physiology that can affect drug disposition, possibly leading to therapeutic failure or toxic side effects. The depth of available literature regarding obesity's effect on drug safety, pharmacokinetics, and dosing in obese children is unknown.ObjectiveTo perform a systematic literature review describing the current evidence of the effect of obesity on drug disposition in children.Evidence reviewWe searched the MEDLINE, Cochrane, and EMBASE databases (January 1, 1970-December 31, 2012) and included studies if they contained data on drug clearance, volume of distribution, or drug concentration in obese children (aged ≤18 years). We compared exposure and weight-normalized volume of distribution and clearance between obese and nonobese children. We explored the association between drug physicochemical properties and clearance and volume of distribution.FindingsTwenty studies met the inclusion criteria and contained pharmacokinetic data for 21 drugs. The median number of obese children studied per drug was 10 (range, 1-112) and ages ranged from newborn to 29 years (1 study described pharmacokinetics in children and adults together). Dosing schema varied and were either a fixed dose (6 [29%]) or based on body weight (10 [48%]) and body surface area (4 [19%]). Clinically significant pharmacokinetic alterations were observed in obese children for 65% (11 of 17) of the studied drugs. Pharmacokinetic alterations resulted in substantial differences in exposure between obese and nonobese children for 38% (5 of 13) of the drugs. We found no association between drug lipophilicity or Biopharmaceutical Drug Disposition Classification System class and changes in volume of distribution or clearance due to obesity.Conclusions and relevanceConsensus is lacking on the most appropriate weight-based dosing strategy for obese children. Prospective pharmacokinetic trials in obese children are needed to ensure therapeutic efficacy and enhance drug safety.
| S-EPMC4494887 | biostudies-literature
Project description:ObjectiveObesity is strongly associated with incident gout risk, but its association with the risk of recurrent gout attacks has been null or weak, constituting an obesity paradox. We sought to demonstrate and overcome the methodologic issues associated with the obesity paradox for risk of recurrent gout attacks.MethodsUsing the Multiple Risk Factor Intervention Trial database, we decomposed the total effect of obesity into its direct and indirect (i.e., mediated) effects using marginal structural models. We also estimated the total effect of body mass index (BMI) change from baseline among incident gout patients.ResultsOf 11,816 gout-free subjects at baseline, we documented 408 incident gout cases, with 132 developing recurrent gout attacks over a 7-year followup period. The adjusted odds ratio (OR) for incident gout among obese individuals was 2.6, whereas that for recurrent gout attacks among gout patients was 0.98 (i.e., the obesity paradox). These ORs correlated well with the ORs for the indirect and direct effects of obesity on the risk of recurrent gout attacks (2.83 and 0.98, respectively). Compared with no BMI change, the OR of increasing versus decreasing >5% of baseline BMI was 0.61 and 1.60 for recurrent gout attacks, respectively (P for trend < 0.01), suggesting a dose-response association.ConclusionThe obesity paradox for the risk of recurrent gout attacks is explained by the absence of the direct effect, which is often measured in conventional analyses and misinterpreted as the intended total effect of interest. In contrast, the BMI change analysis correctly estimated the intended total effect of BMI, and revealed a dose-response relationship.
| S-EPMC5179319 | biostudies-literature
Project description:BACKGROUND/OBJECTIVES:Experiments in animal models have shown a positive association between in utero exposure to pharmacologic sex hormones and offspring obesity. The developmental effects of such hormones on human obesity are unknown. SUBJECTS/METHODS:Using data from a large, prospective pregnancy cohort study (n=19?652), with linkage to a national prescription registry, we evaluated the association between use of hormonal contraceptives before and after conception (defined from dispensed prescription data and characterized by last date of use relative to conception, 12 to >4 months before (n=3392), 4 to >1 months before (n=2541), 1 to >0 months before (n=2997) and 0-12 weeks after (n=567)) in relation to offspring overweight or obesity at age 3 years. RESULTS:We observed a weak, inverse association between early pregnancy use of a combination oral contraceptive and offspring overweight or obesity at age 3 (adjusted odds ratio (OR): 0.75, 95% confidence interval (CI): 0.53, 1.08) and a positive, but imprecise, association with use of a progestin-only oral contraceptive in early pregnancy (adjusted OR: 1.26, 95% CI: 0.79, 2.02). In general, no association was observed between the use of a hormonal contraceptive before conception and offspring overweight or obesity. A sensitivity analysis comparing combination oral contraceptive users in early pregnancy to other unplanned pregnancies without hormonal contraceptive use further strengthened the inverse association (adjusted OR: 0.70, 95% CI: 0.48, 1.02). Other sensitivity analyses were conducted to evaluate the robustness of the associations observed given varying assumptions. CONCLUSIONS:Pharmacologic sex hormones in early pregnancy may be inversely or positively associated with offspring overweight or obesity at age 3, depending on the specific formulation used. The present study provides support for the potential for environmental sources of hormonally active agents to exert developmental effects.
| S-EPMC4365991 | biostudies-literature
Project description:PurposeAntiepileptic 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.MethodsA 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 findingsWe 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).SignificanceA 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.
| S-EPMC3057928 | biostudies-literature
Project description:ObjectiveTo estimate associations between contraceptive failures and concomitant CYP3A4-inducing medications by route of administration.Study designComparison of unintended pregnancy outcomes within U.S. Food and Drug Administration's Adverse Event Reporting System by couse of CYP3A4-inducing drugs and route of administration for levonorgestrel and etonogestrel/desogestrel.ResultsAmong 14,504 levonorgestrel case reports, the reporting odds ratio (ROR) was increased for oral (ROR = 4.2 [3.0-5.7]), implants (ROR = 8.0 [5.8-11.0]), but not intrauterine (ROR = 0.9 [0.6-1.3]) levonorgestrel products. For 9348 etonogestrel/desogestrel case reports, oral and vaginal products were not associated with contraceptive failure. Etonogestrel containing implants (ROR = 4.9 [4.1-5.9]) were associated with increased contraceptive failure.ConclusionLevonorgestrel containing combination oral products and implants containing levonorgestrel or etonogestrel were prone to CYP3A4-inducing drug-drug interactions that may increase contraceptive failures.ImplicationsThe progestin components of hormonal contraceptives are susceptible to drug-drug interactions, but this susceptibility is influenced by route of administration. This study provides evidence from an Adverse Event Reporting System that CYP3A4-inducing medications increase the risk of unintended pregnancy for oral and implant contraceptives but not intrauterine or vaginal devices.
| S-EPMC7972989 | biostudies-literature
Project description:Adjudin, also known as AF-2364 and an analog of lonidamine (LND), is a male contraceptive acting through the induction of premature sperm depletion from the seminiferous epithelium when orally administered to adult rats, rabbits or dogs. It is also known that LND can target mitochondria and block energy metabolism in tumor cells. However, whether Adjudin exhibits any anti-cancer activity remains to be elucidated. Herein we described the anti-proliferative activity of Adjudin on cancer cells in vitro and on lung and prostate tumors inoculated in nude mice. We found that Adjudin induced apoptosis in cancer cells through a Caspase-3-dependent pathway. Further experiments revealed that Adjudin could trigger mitochondrial dysfunction in cancer cells, apparently affecting the mitochondrial mass, inducing the loss of mitochondrial membrane potential and reducing cellular ATP levels. Intraperitoneal administration of Adjudin to tumor-bearing athymic nude mice also significantly suppressed the lung and prostate tumor growth. When used in combination with cisplatin, Adjudin enhances the sensitivity to cisplatin-induced cancer cell cytotoxicity. Taken together, these findings have demonstrated that Adjudin may be a potential drug for cancer therapy.
| S-EPMC4108200 | biostudies-literature
Project description: Not available
| S-EPMC5519255 | biostudies-literature
Project description:Vortioxetine is a novel antidepressant with multimodal activity currently approved for the treatment of major depressive disorder. Vortioxetine is orally administered once daily at 5- to 20-mg doses. The pharmacokinetics of vortioxetine are linear and dose proportional, with a mean terminal half-life of approximately 66 h and steady-state plasma concentrations generally achieved within 2 weeks of dosing. The mean absolute oral bioavailability of vortioxetine is 75%. No food effect on pharmacokinetics was observed. Vortioxetine is metabolized by cytochrome P450 enzymes and subsequently by uridine diphosphate glucuronosyltransferase. The major metabolite is pharmacologically inactive, and the minor pharmacologically active metabolite is not expected to cross the blood-brain barrier, making the parent compound primarily responsible for in-vivo activity. No clinically relevant differences were observed in vortioxetine exposure by sex, age, race, body size, and renal or hepatic function. Dose adjustment is only recommended for cytochrome P450 2D6 poor metabolizers based on polymorphism of the cytochrome P450 enzymes involved. Similarly, except for bupropion, a strong cytochrome P450 2D6 inhibitor, and rifampin, a broad cytochrome P450 inducer, co-administration of other drugs evaluated did not affect the vortioxetine exposure or safety profile in any clinically meaningful way. Pharmacodynamic studies demonstrated that vortioxetine achieved high levels of serotonin transporter occupancy in relevant brain areas, affected neurotransmitter levels in the cerebrospinal fluid, and modified abnormal resting state networks in the brain over the therapeutic dose range. Overall, vortioxetine can be administered in most populations studied to date without major dose adjustments; however, dose adjustments should be considered on a patient-by-patient basis.
| S-EPMC5973995 | biostudies-literature
Project description:Considerable interest remains across the pharmaceutical industry and regulatory landscape in capabilities to model oral contraceptives (OCs), whether combined (COCs) with ethinyl estradiol (EE) or progestin-only pill. Acceptance of COC drug-drug interaction (DDI) assessment using physiologically-based pharmacokinetic (PBPK) is often limited to the estrogen component (EE), requiring further verification, with extrapolation from EE to progestins discouraged. There is a paucity of published progestin component PBPK models to support the regulatory DDI guidance for industry to evaluate a new chemical entity's (NCE's) DDI potential with COCs. Guidance recommends a clinical interaction study to be considered if an investigational drug is a weak or moderate inducer, or a moderate/strong inhibitor, of CYP3A4. Therefore, availability of validated OC PBPK models within one software platform, will be useful in predicting the DDI potential with NCEs earlier in the clinical development. Thus, this work was focused on developing and validating PBPK models for progestins, DNG, DRSP, LNG, and NET, within Simcyp, and assessing the DDI potential with known CYP3A4 inhibitors (e.g., ketoconazole) and inducers (e.g., rifampicin) with published clinical data. In addition, this work demonstrated confidence in the Simcyp EE model for regulatory and clinical applications by extensive verification in 70+ clinical PK and CYP3A4 interaction studies. The results provide greater capability to prospectively model clinical CYP3A4 DDI with COCs using Simcyp PBPK to interrogate the regulatory decision-tree to contextualize the potential interaction by known perpetrators and NCEs, enabling model-informed decision making, clinical study designs, and delivering potential alternative COC options for women of childbearing potential.
| S-EPMC11015076 | biostudies-literature
Project description:PurposeThe aim of this study was to evaluate ceftazidime pharmacokinetics (PK) in a cohort that includes a predominate number of children and adolescents with obesity and assess the efficacy of competing dosing strategies.MethodsA population PK model was developed using opportunistically collected plasma samples. For each dosing strategy, model-based probability of target attainment (PTA) estimates were computed for study participants using empirical Bayes estimates. In addition, the effects of body size and renal function on PTA were evaluated using stochastic model simulations with virtually generated subjects.ResultsTwenty-nine participants, 24 of whom were obese, contributed data towards the analysis. The median (range) age, body weight, and body mass index of participants were 12.2 years (2.3-20.6), 59.2 kg (8.4-121), and 25.2 kg/m2 (13.8-42.9), respectively. Administration of 50 mg/kg intravenously (IV) every 8 hours (q8h; max 6 g/day) or 40 mg/kg IV q6h (max 6 g/day) resulted in PTA values of ≥ 90% (minimum inhibitory concentration 8 mg/L) for the subset of obese participants with estimated glomerular filtration rates (GFR) ≥ ~ 80 mL/min/1.73 m2. However, for both regimens, stochastic model simulations denoted lower PTA values (< 90%) with increasing body weight for virtual subjects with GFR ≥ 120 mL/min/1.73 m2. Alternatively, permitting for a maximum daily dose of 8 g/day using a 40 mg/kg IV q6h regimen provided PTA values that were near or above target (90%) for virtual subjects between 10 to 120 kg with GFR ≥ 80 mL/min/1.73 m2.ConclusionOur analysis suggests administration of 40 mg/kg IV q6h (max 8 g/day) maximizes PTA in children and adolescents with obesity and GFR ≥ 80 mL/min/1.73 m2.Trial registrationClinicaltrials.gov Identifier: NCT01431326.
| S-EPMC9706343 | biostudies-literature