Nguyen Quyen T. X.(2), Petricoul O.(1), Cerutti B.(2), Maislich L. (2), Loumaye E.(2), Munafo A.(2)
(1) EMF Consulting, Aix-en-Provence, France; (2) Serono International SA, Geneva, Switzerland
Background. Hypogonadism due to hypothalamic, pituitary or testicular failure, may be observed in patients with HIV infection Testosterone deficiency causes loss of weight, loss of energy, anaemia, affects the mood and induces sexual dysfunction. Testosterone derivatives and human chorionic gonadotrophin (hCG) are the two agents indicated for increasing serum testosterone levels in male hypogonadotropic hypogonadism. Human Chorionic Gonadotrophin can be obtained by extraction from the urine of pregnant women or obtained by recombinant technology. The latter (r-hCG) was used in this clinical trial.
Objectives. The purpose of this analysis was to describe the pharmacokinetics of r-hCG, Ovidrel, and to describe the relationship between r-hCG concentrations and testosterone levels in HIV males with hypogonadotropic hypogonadism.
Methods. r-hCG and testosterone levels were collected in a phase II, dose ranging study. Thirty-nine patients received subcutaneously either r-hCG (125 mg, 250 mg or 500 mg) or placebo twice a week (at interval of 3 to 4 days) during 12 weeks. PK and PK/PD population modelling, using NONMEM version V, were used to describe concentrations of hCG and the relationship to testosterone serum levels.
Results. A one-compartment disposition model with first order absorption and elimination with a proportional error variance model best described the kinetics of hCG. The absorption half-life was around 2 h, CL/F was 0.57 L/h and V/F was 61 L. The apparent clearance happened to be higher in the 125 µg dose group, but this effect could be confounded with the duration of HIV infection, which was also found to affect this parameter. Indeed, patients included in the 125 µg group had significantly higher HIV duration compared to the other treatment groups. The best model to describe the serum testosterone level consisted of a PK/PD model with a constant baseline value, a direct relationship between hCG serum level and testosterone serum level with additive residual error. The relationship between hCG and testosterone was an all-or-nothing effect of the drug with a threshold hCG concentration of 1 mg/L. The effect of the drug was an increase of testosterone serum level of 10.2 nmol/L, giving a total testosterone level of 22.8 nmol/L. This level was reached at the first efficacy assessment, after 2 weeks of treatment. Conclusion. All active treatments provided on week 2 and thereafter, hCG concentrations associated with serum testosterone within the normal range .
Reference: PAGE 10 () Abstr 192 [www.page-meeting.org/?abstract=192]
Poster: poster