Effect of age/menopause on lopinavir and efavirenz concentrations in women
15 June 2005. Related: Conference reports, Women's health, PK Workshop 6th 2005.
Polly Clayden, HIV i-Base
Protease inhibitors and non-nucleoside reverse transcriptase inhibitors are extensively metabolised by CYP3A4. Previous research has shown that CYP3A4 activity declines with age particularly in people over 65 and this should result in higher drug concentrations. The intestinal content of this enzyme has been shown to be 20% lower in post menopausal than pre-menopausal women. [1, 2]
A poster authored by Sarah Gibbons and colleagues from Liverpool University showed findings from a study evaluating the effect of age/menopausal status on plasma concentrations of lopinavir and efavirenz substrates of CYP3A4 and CYP2B6 (which is the primary metaboliser of efavirenz). [3]
This was a retrospective analysis performed using requests for the Liverpool TDM service from non-pregnant women receiving lopinavir (plasma concentrations measured 10 to 14 hours post dose) and efavirenz (8 to16 hours post dose).
Plasma concentrations were measured by HPLC-MS/MS and results <100 ng/mL excluded as these could be due to non-adherence. Samples were stratified by age: pre-menopausal <40 years, peri-menopausal 40 to 50 years and post-menopausal >50 years.
Results were available from 116 women using lopinavir and 141 women using efavirenz, and are shown in Table 1.
Table 1: Lopinavir and efavirenz plasma concentrations
| Plasma concentrations (ng/ml) | |||
| n | Median | IQR | |
| Lopinavir | |||
| Pre-menopausal | 68 | 6786 | 3620-9112 |
| Peri-menopausal | 41 | 7142 | 4843-8928 |
| Post-menopausal | 7 | 5621 | 3518-6647 |
| Efavirenz | |||
| Pre-menopausal | 85 | 1990 | 1500-3361 |
| Peri-menopausal | 38 | 1847 | 1416-3025 |
| Post- menopausal | 18 | 2516 | 2135-4092 |
The authors reported no statistically significant differences in lopinavir concentrations between the groups (pre and peri-menopausal p=0.664; pre and post-menopausal p=0.211) using Mann Whitney tests.
For efavirenz they found a statistically significant difference between pre and post-menopausal groups (p=0.046) but not between pre and peri-menopausal (p=0.630)
The report acknowledged that using age as an indicator of menopausal status and the possible absence of information on steroid contraception or hormone replacement therapy use limited the analysis. The authors conclude: CYP2B6 activity may be affected by age and/or menopausal state but this would only be confirmed in a controlled study.
References:
- Wilkinson GR. The effects of diet, aging and disease states on presystemic elimination and oral drug bioavailabilty in humans. Advanced Drug Delivery Reviews 1997, 27:129-159.
- Paine MF, Ludington SS, Chen ML, et al. Do men and women differ in proximal small intestinal CYP3A or P-glycoprotein expression? Drug Metab Dispos 2005;33:426-433.
- Gibbons SE, Back DJ, Khoo SH et al. Is there evidence of age-dependent variation in lopinavir or efavirenz levels in female subjects in the clinical setting? 6th International Workshop on Clinical Pharmacology of HIV Therapy. 28-30 April 2005. Quebec. Abstract 54.