Biomedical subjects

Lynn McFadyen

Publications and source records attributed to Lynn McFadyen.

7 recordsLinked to original sources

PubMed2006

Modeling and simulation of sexual activity daily diary data of patients with female sexual arousal disorder treated with sildenafil citrate (Viagra).

PURPOSE: To develop a model to explore the dose-response of sildenafil citrate in patients with female sexual arousal disorder (FSAD) based on telephone sexual activity daily diary (TSADD) data obtained in double-blind, placebo controlled clinical studies. MATERIALS: Data were available on 614 patients with FSAD. A parametric model (Weibull distribution) was developed to describe the probability density function of the time between sexual events. Orgasm satisfaction scores and overall sexual satisfaction scores were simultaneously modeled as ordered categorical variables. Simulations were performed to evaluate the expected clinical response in patients with FSAD. RESULTS: The expected time between sexual events was approximately 3.5 days. Satisfaction scores increased with time to achieve a plateau after 3 to 4 weeks on treatment. The expected probability of satisfying orgasm (score of 3 and higher) ranged from 34.7% for placebo to 41.6% for 100 mg sildenafil citrate. Treatment effect (difference from placebo) was 6.9% for 100 mg sildenafil citrate, ranging from 0.6 to 24.7% for testosterone levels of 0.1 to 4.0 pg/ml. The treatment effect in postmenopausal women was larger than in premenopausal women. CONCLUSION: A modeling and simulation framework to support drug development in FSAD was developed. Sildenafil citrate demonstrated a dose-dependent effect in patients with FSAD.

Adult↗

PubMed2005

Population pharmacokinetics of rifapentine and its primary desacetyl metabolite in South African tuberculosis patients.

This study was designed to describe the population pharmacokinetics of rifapentine (RFP) and 25-desacetyl RFP in a South African pulmonary tuberculosis patient population. Special reference was made to studying the influence of previous exposure to rifampin (RIF) and the variability in pharmacokinetic parameters between patients and between occasions and the influence of different covariates. Patients were included in the study if they had been receiving first-line antimycobacterial therapy (rifampin, isoniazid, pyrazinamide, and ethambutol) for not less than 4 weeks and not more than 6 weeks and were divided into three RFP dosage groups based on weight: 600 mg, <45 kg; 750 mg, 46 to 55 kg; and 900 mg, >55 kg. Participants received a single oral dose of RFP together with concomitant antimycobacterial agents, excluding RIF, on study days 1 and 5 after they ingested a soup-based meal. The RFP and 25-desacetyl RFP concentration-time data were analyzed by nonlinear mixed-effect modeling using NONMEM. The pharmacokinetics of the parent drug were modeled separately, and the individual pharmacokinetic parameters were used as inputs for the 25-desacetyl RFP pharmacokinetic model. A one-compartment disposition model was found to best describe the data for both the parent and the metabolite, and the metabolite was assumed to be formed only from the central compartment of the parent drug. Prior treatment with RIF did not alter the pharmacokinetics of RFP but appeared to increase the excretion of 25-desacetyl RFP in a nonlinear fashion. The RFP oral clearance and volume of distribution were found to increase by 0.049 liter/h and 0.691 liter, respectively, with a 1-kg increase from the median weight of 50 kg. The oral clearance of 25-desacetyl RFP was found to be 35% lower in female patients. The model developed here describes the population pharmacokinetics of RFP and its primary metabolite in tuberculosis patients and includes the effects of prior administration with RIF and covariate factors.

Adult↗

PubMed2004

Serum medroxyprogesterone acetate levels in new and repeat users of depot medroxyprogesterone acetate at the end of the dosing interval.

In the absence of published data on serum medroxyprogesterone acetate (MPA) levels in South African users, this study examines such levels in new and repeat users of depot medroxyprogesterone acetate at the end of the dosing interval. The study was undertaken at three family-planning clinics in Durban, South Africa. Serum MPA levels were measured in 94 Black African, Indian and White women returning between 11 and 14 weeks after their last injection. The median serum MPA level was 0.88 (range, <0.04-1.77) ng/mL and wide interindividual variability was observed. Levels in all but one woman were higher than 0.1 ng/mL, the level at which ovulation is reported to resume. MPA levels were not found to vary according to weight, body mass index or ethnicity. Although there was a slight tendency towards higher MPA levels with longer duration of use (r = 0.13), the wide interindividual variability precluded the possibility of determining whether this was a real trend. A prospective study, using standardized assay techniques and following individual women, is required to further clarify this issue.

Adolescent↗

PubMed2003

A two-part mixture model for longitudinal adverse event severity data.

We fit a mixed effects logistic regression model to longitudinal adverse event (AE) severity data (four-point ordered categorical response) to describe the dose-AE severity response for an investigational drug. The distribution of the predicted interindividual random effects (Bayes predictions) was extremely bimodal. This extreme bimodality indicated that biased parameter estimates and poor predictive performance were likely. The distribution's primary mode was composed of patients that did not experience an AE. Moreover, the Bayes predictions of these non-AE patients were nearly degenerative, i.e., the predictions were nearly identical. To resolve this extreme bimodality we propose using a two-part mixture modeling approach. The first part models the incidence of AE's, and the second part models the severity grade given the patient had an AE. Unconditional probability predictions are calculated by mixing the incidence and severity model probability predictions. We also report results of simulation studies, which assess the predictive and statistical (bias and precision) performance of our approach.

Bayes Theorem↗

PubMed2003

Population pharmacokinetics of levosimendan in patients with congestive heart failure.

AIMS: The aim of this study was to characterize the population pharmacokinetics of levosimendan in patients with heart failure (NYHA grades III and IV) and its relationship to demographic factors, disease severity and concomitant use of digoxin and beta-blocking agents. METHODS: Data from two efficacy studies with levosimendan administered by intravenous infusion were combined (190 patients in total). The data were analysed using a nonlinear mixed-effects modelling approach as implemented in the NONMEM program. The model development was done in three sequential steps. First the best structural model was determined (e.g. a one-, two- or three-compartment pharmacokinetic model). This was followed by the identification and incorporation of important covariates into the model. Lastly the stochastic part of the model was refined. RESULTS: A two-compartment model best described levosimendan pharmacokinetics. Clearance and the central volume of distribution were found to increase linearly with bodyweight. No other covariates, including concomitant use of digoxin and beta-blocking agents, influenced the pharmacokinetics. In the final model, a 76-kg patient was estimated to have a clearance +/- s.e. of 13.3 +/- 0.4 l h-1 and a central volume of distribution of 16.8 +/- 0.79 l. The interindividual variability was estimated to be 39% and 60% for clearance and central volume of distribution, respectively. Weight changed clearance by 1.5% [95% confidence interval (CI) 0.9%, 2.1%] and the central volume of distribution by 0.9% (95% CI 0.5%, 1.3%) per kg. CONCLUSIONS: The population pharmacokinetics parameters of levosimendan in this patient group were comparable to those obtained by traditional methods in healthy volunteers and patients with mild heart failure. Bodyweight influenced the clearance and the central volume of distribution, which in practice is accounted for by weight adjusting doses. None of the other covariates, including digoxin and beta-blocking agents, significantly influenced the pharmacokinetics of levosimendan.

Adrenergic beta-Antagonists↗

PubMed2003

Dual protection against sexually transmitted infections and pregnancy in South Africa.

Promotion of simultaneous protection against sexually transmitted infections (STIs) and unintended pregnancy, referred to as dual protection, represents an important public health intervention. We investigated its prevalence and correlates in South Africa. A cross-sectional survey of 929 sexually active women, aged 15-49 years, was conducted in 89 public primary health care clinics, with dual method use and use of condom alone at last sexual intercourse as outcomes. At last intercourse, 12% of women were protected from both STIs and pregnancy. In multivariate analysis, higher education, being unmarried, and multiple sex partnership in the past year were predictors of dual method use, while younger age, higher education and awareness of the dual function of condoms were predictors of condom use alone. Dual protection is low in this population. The predominance of hormonal contraceptive use in South Africa means that increasing barrier method use among hormonal contraceptive users is an important strategy for increasing dual protection.

Adolescent↗

PubMed2002

Vaginal wetness: an underestimated problem experienced by progestogen injectable contraceptive users in South Africa.

This paper reports on the common experience of vaginal wetness amongst South African users of progestogen-only injectable contraceptives. The observations emerged in the course of a community-based cross-sectional household survey undertaken in a rural district of KwaZulu-Natal in South Africa. The purpose of the survey was to elicit self-reporting on side effects of injectable contraceptive methods. Eight hundred and forty-eight women aged 15-49 were interviewed and 22.1% reported current use of an injectable contraceptive method, either depot medroxyprogesterone acetate (Depo-Provera) or norethisterone oenanthate (Nur-Isterate). Other modern methods used were oral hormonal contraceptives (4.5%), male condoms (1.3%), the intrauterine device (0.1%), and tubal ligation (0.1%). Vaginal wetness was reported by 18.4% of users and was one of the most common side effects, second only to amenorrhoea (62.5%). It was also what 17.5% of the women liked least about using this method. According to almost half the respondents, men regard women who use the injectable contraceptive as "wet", "cold" and/or "tasteless". These survey findings were supported by participants of 14 focus group interviews held in the sub-district. Since some South African men may prefer dry sex the perception that the injectable contraceptive increases vaginal wetness may be problematic for women who use it. Whilst vaginal wetness can only be classified as a subjective side effect at this stage, further investigations are needed as many South African women opt to use this method.

Adolescent↗