Tenofovir plasma concentrations in post-menopausal versus pre-menopausal HIV-infected women

Abstract

Sir, Menopause is associated with age-related physiological changes—such as a decline in renal and hepatic function, altered genital secretions and/or impaired production of sexual hormones—that can potentially affect the disposition of several drugs. The role of menopause on the pharmacokinetics of antiretrovirals, however, has not been investigated so far. Given the potential impact of tenofovir on long-term kidney and bone complications, which are known co-morbidities affecting post-menopausal women, we decided to perform a retrospective analysis of data from post-menopausal and premenopausal HIV-infected women receiving 300 mg of tenofovir/day as part of their maintenance antiretroviral therapy regimen for at least 3 months who underwent therapeutic drug monitoring of tenofovir plasma trough concentrations as routine outpatient follow-up. Menopause was established by menstrual and medical history (12 months of lack of menstrual cycle for women aged 50 years or more, with hormonal confirmation for women younger than 50 years). Creatinine clearance was calculated by using the formula of Cockcroft–Gault as follows: glomerular filtration rate1⁄4 (1402age)×body weight/ serum creatinine×72. As the patients were female, the formula was multiplied by a constant of 0.85. As per our clinical practice, tenofovir plasma trough concentrations were collected immediately before the following morning’s tenofovir dose (a time window of +5 min was considered as acceptable). For patients given tenofovir once daily in the evening, plasma trough (24 h) concentrations were estimated from the concentrations collected at 12 h after drug intake and taking into account the terminal portion of the pharmacokinetic drug profile. Tenofovir concentrations were assessed by a validated liquid chromatography–tandem mass spectrometry (‘LC-MS/MS’) method. A total of 50 HIV-infected women were identified from our database: 22 were post-menopausal women, while the remaining 28 were pre-menopausal women. A wide distribution of plasma tenofovir trough concentrations was observed when considering the data from the overall study population (n1⁄450, tenofovir concentrations ranged from 10 to 452 ng/mL). We first compared tenofovir plasma trough concentrations, together with demographic and haemato-chemical characteristics, in the post-menopausal women (n1⁄422) versus the pre-menopausal women (n1⁄428). As shown in Table 1, no major differences were observed between the two groups of patients in terms of concomitant antiretroviral therapy, kidney and liver function, as well as for other demographic characteristics with the (expected) exceptions of age and time on tenofovir therapy. It is worth mentioning that tenofovir plasma concentrations measured in post-menopausal women exactly matched those assessed in pre-menopausal women (119+64 versus 121+98 ng/mL, P1⁄40.924). In order to further investigate the potential effect of menopause on tenofovir exposure, we also performed multiple regression analysis in the overall population (n1⁄450) using tenofovir plasma trough concentrations as the dependent variable and menopause, serum transaminase, serum creatinine, age, body weight, concomitant antiretroviral therapy and days on tenofovir therapy as independent covariates. Using this approach we found that the only factors independently associated with tenofovir plasma concentrations were serum creatinine (r1⁄40.411, P1⁄40.043) and body weight (r1⁄420.432, P1⁄40.021), whereas no effect of menopause was documented (r1⁄420.049, P1⁄40.852). This trend was also confirmed when using creatinine clearance (r1⁄420.384, P1⁄40.022) and body mass index (r1⁄420.305, P1⁄40.037) instead of serum creatinine and body weight, respectively. Taken together, our results argue against a significant effect of menopause on tenofovir exposure. These findings are at odds with those presented by Patterson et al., who reported significantly higher (up to 160%) tenofovir plasma and genital tract concentrations in 6 post-menopausal versus 12 pre-menopausal African American HIV-infected women. The discrepant results of Research letters