Cobicistat Has Little Impact on CYP2D6 and CYP2B6

Cobicistat, the boosting agent being developed for combination with the integrase inhibitor elvitegravir and protease inhibitors, had little impact on two key drug-metabolizing enzymes (CYP2D6 and CYP2B6) or on the drug transporter P-glycoprotein, according to results of a three-part study by Gilead Sciences.¹

In a phase 2 trial, a once-daily single pill coformulation of elvitegravir/cobicistat plus tenofovir/emtricitabine controlled viral replication as well as Atripla, the once-a-day one-pill combination of efavirenz, tenofovir, and emtricitabine, through 48 weeks in previously untreated people.² Average elvitegravir trough concentration in that study exceeded the protein binding-adjusted 95% inhibitory concentration of elvitegravir by a factor of 10. In a 44-person pharmacokinetic study, cobicistat boosted elvitegravir to levels equivalent to those reached with ritonavir boosting.³ Unlike ritonavir, cobicistat has no anti-HIV activity.

Cobicistat is a strong inhibitor of CYP3A, but earlier studies showed that it does not inhibit the enzymes CYP1A2, CYP2C8, CYP2C9, or CYP2C19 and that it is a weak inhibitor of CYP2D6 and P-glycoprotein. The new study evaluated the impact of cobicistat on drugs whose metabolism is strongly affected by CYP2D6 (desipramine), CYP2B6 (efavirenz), or P-glycoprotein (digoxin).

Researchers enrolled 10 people in the desipramine group, 25 in the digoxin group, and 18 in the efavirenz group. Study participants took 150 mg of cobicistat or the probe drug (desipramine, efavirenz, or digoxin) in one of two sequences: (1) cobicistat once daily for 9 day, then one dose of cobicistat and one dose of the probe drug, then a washout period with no drugs, than one dose of the probe drug, or (2) one dose of the probe drug, a washout, cobicistat once daily for 9 days, then one dose of cobicistat and one dose of the probe drug.

Nine people originally assigned to desipramine, 22 assigned to digoxin, and 17 assigned to efavirenz completed the study. Ages averaged 35 in the desipramine group, 33 in the digoxin group, and 33 in the efavirenz group. Respective average weights were 76 kg, 71 kg, and 74 kg. About two thirds of volunteers were white.

Most treatment-emergent toxicities were mild (grade 1), except for a single case of treatment-emergent gastroesophageal reflux after 9 days in the digoxin group that required withdrawal from the study.

Coadministration of cobicistat with desipramine led to a 58% to 65% increase in desipramine area under the concentration-time curve (AUC) and to a 24% increase in desipramine maximum concentration (Cmax). Efavirenz Cmax fell about 13% with cobicistat, while digoxin Cmax rose about 41%. Efavirenz and digoxin AUC changed little with cobicistat. When taken with the probe drugs, cobicistat reached levels similar to those recorded in earlier studies of this boosting agent.

The Gilead team concluded that cobicistat may be classified as a weak CYP2D6 inhibitor since desipramine exposure rose less than 2-fold with cobicistat. The lower efavirenz Cmax and higher digoxin Cmax with cobicistat appear not to require dose modifications.

The investigators believe that additional drug-drug interaction studies are not needed to explore the impact of cobicistat on drugs affected by CYP2D6, CYP2B6, or P-glycoprotein.

References

1. German P et al. The effect of cobicistat on cytochrome P450 2D6, 2B6 and P-glycoprotein using phenotypic probes. 12th International Workshop on Clinical Pharmacology of HIV Therapy, 13–15 April 2011, Miami. Oral abstract O_01.
2. Cohen C et al. Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection. AIDS. 2011;25:F7-F12.
3. German P et al. Pharmacokinetics and bioavailability of an integrase [inhibitor] and novel pharmacoenhancer-containing single-tablet fixed-dose combination regimen for the treatment of HIV. J Acquir Immune Defic Syndr. 2010;55:323-329.

Mark Mascolini is with NATAP.org.