Modelling and Simulation of the Telephone Sexual Activity Daily Diary (TSADD) Data of patients with female sexual arousal disorder (FSAD) treated with sildenafil (Viagra).

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Objectives: To develop models to:
i) Characterize the probability of sexual events and their satisfaction scores over time based on TSADD data obtained in Phase 2b/3 clinical studies of sildenafil in patients with FSAD without concomitant Hypoactive Sexual Desire Disorder (HSDD).
ii) Simulate the expected dose-response in various patient populations to assess the impact of patient and disease characteristics on outcome.

Methods: Data were available on 493 patients with FSAD from three clinical studies. A parametric model was developed to describe the probability density function of the time between sexual events. Orgasm satisfaction scores (OS) and overall sexual satisfaction (SS) scores were modelled as 4 level-ordered categorical variables. The models were implemented in NONMEM. The following covariate effects were assessed (log-likelihood ratio test at p < 0.05): drug intake, drug dose, age, baseline diagnostic and satisfaction scores, menopausal status, and hormone levels. The models were qualified by posterior predictive check. Initial simulations were performed to evaluate the expected clinical response in the FSAD patient population.

Results: A Weibull distribution best described the probability density function of the time between sexual events. The median time between sexual events was 3 days and was not influenced by sex or orgasm satisfaction scores. Satisfaction scores were simultaneously modelled with overall sexual satisfaction conditional on orgasm satisfaction (P(SS|OS)).

• Satisfaction scores increased with time on study in a nonlinear fashion to achieve a plateau after 3 to 4 weeks on treatment.
• Sildenafil effect was dependent on dose, testosterone level and menopausal status.
• The probability of orgasm satisfaction scoring rates of 3 and higher was used as the clinical endpoint for simulations. The orgasm satisfaction rate ranged from 34.7% for placebo to 41.6% for 100 mg sildenafil. Absolute treatment effect (difference from placebo) was 6.9% for 100 mg dose of sildenafil, ranging from 0.6 to 24.7% for testosterone levels of 0.1 to 4pg/ml, respectively. The treatment effect for sildenafil in post-menopausal women was larger than in pre-menopausal women.

Conclusion:  A modelling & simulation framework to support drug development in FSAD was developed. Sildenafil demonstrated a dose-dependent effect in female patients with FSAD.