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Inhibition of CYP3A7 by Ritonavir and Lopinavir Leads to Adrenal Insufficiency in the Developing Infant by Blocking DHEA‐S Oxidation

CYP3A7 is the predominant CYP3A isoform in the neonate and developing infant. Its primary function is the 16α‐hydroxylation of the endogenous hormone DHEA‐S, which is important for downstream maintenance of hormone homeostasis in the adrenal gland. Newborns infected with HIV are typically treated with a combination therapy of Lopinavir and the pharmacokinetic enhancer Ritonavir. However, adrenal insufficiency due to increased DHEA‐S concentrations, and premature birth, have been reported in this treatment population, leading to adverse outcomes in this fragile patient group. Given that Ritonavir is a known potent inhibitor of CYP3A4, we hypothesized that it might also be an inhibitor of CYP3A7‐mediated DHEA‐S oxidation and that this inhibition might be responsible for the adrenal insufficiency and other side effects associated with Lopinavir‐Ritonavir treatment. Indeed, we observed significant inhibition of CYP3A7 DHEA‐S hydroxylation activity in the presence of Ritonavir with an IC50 of 0.05 μM. Furthermore, Ritonavir displayed time‐dependent inhibition of DHEA‐S oxidation, with a Ki of 0.336 μM and a Kinact of 0.1077 min−1, suggesting that it may be a mechanism based inactivator of CYP3A7. Lopinavir was also capable of inhibiting CYP3A7, albeit to a much lesser extent than Ritonavir with an IC50 of 5.88 μM for DHEA‐S 16α‐hydroxylation, and without the associated time‐dependency. Interestingly, Lopinavir alone has a much higher intrinsic clearance rate in fetal liver microsomes compared to adult liver microsomes, indicating the need for a pharmacokinetic enhancer adjuvant in order to slow clearance and maintain efficacy. However, our results suggest that closer monitoring of the effective dose of the pharmacokinetic enhancer may be required in order to prevent significant inhibition of CYP3A7 DHEA‐S oxidation and the associated adverse effects.