It is likely that phenobarbital and other barbiturates will increasethe metabolism of protease inhibitors, thereby reducing theirlevels and possibly resulting in failure of antiretrovirals. However,one case suggested that this may not have occurred withprimidone and ritonavir/saquinavir, although this should beviewed with caution.
Clinical evidence,mechanism, importance and management
The manufacturers of many of protease inhibitors predict that their levels may be reduced by phenobarbital, due to induction of cytochrome P450 isoenzyme CYP3A4 by which they are metabolised (see table 1 below,). There do not appear to be any controlled studies to demonstrate extent of pharmacokinetic interaction with different pro-tease inhibitors. Data from one case report of carbamazepine toxicity with ritonavir/saquinavir, , provide indirect evidence to suggest interaction with primidone is not clinically important. In this report,a patient taking an antiretroviral regimen including ritonavir and saquinavir had his antiepileptic medication changed from carbamazepine to primidone 500mg daily. The authors noted that during follow-up (duration not stated),viral load was still undetectable and seizures remained under control (See reference number 1). Primidone is metabolised to phenobarbital,and might have been expected to cause antiretroviral therapy failure. Alternatively, effect of ritonavir, which is a potent inhibitor of CYP3A4, may have been sufficient to offset increased clearance associated with phenobarbital.
Another patient(See reference number 2)taking phenobarbital,phenytoin and carbamazepine was found to have an unchanged phenobarbital level 2 days after switching from an antiretroviral regimen including indinavir to one containing ritonavir 300mg twice daily and saquinavir. His plasma levels of carbamazepine,, had doubled, and there was a 32.7 % drop in levels of phenytoin, .
The combination of protease inhibitors and barbiturates should be used with caution,with increased monitoring of antiviral efficacy.
Berbel Garcia A,Latorre Ibarra A, Porta Etessam J, Martinez Salio A, Perez Martinez DA, Saiz Diaz R, Toledo Heras M. Protease inhibitor-induced carbamazepine toxicity. Clin Neuropharmacol (2000) 23, 216–18.
Mateu-de Antonio J, Grau S, Gimeno-Bayón J-L, Carmona A. Ritonavir-induced carbamazepine toxicity. Ann Pharmacother (2001) 35, 125–6.
| Table 1 Summary of the effect of the protease inhibitors and NNRTIs on cy | tochrome P450 isoenzymes | ||
|---|---|---|---|
| Antiviral | Substrate | Inhibits | Induces |
| Protease inhibitors | |||
| Amprenavir or Fosamprenavir | CYP3A4 | CYP3A4 | |
| Atazanavir | CYP3A4 | CYP3A4 | |
| Darunavir | CYP3A4 | CYP3A4 | |
| Indinavir | CYP3A4 | CYP3A4 | |
| Lopinavir | CYP3A4 | CYP3A4 | |
| Nelfinavir | CYP3A4, CYP2C19, CYP2C9, CYP2D6 | CYP3A4 | |
| Ritonavir | CYP3A4, CYP2D6 | CYP3A4, CYP2D6 | CYP3A4 |
| Saquinavir | CYP3A4 | CYP3A4 | |
| Tipranavir | CYP3A4 | CYP3A4, CYP2D6 | CYP3A4 |
| NNRTIs (Non-nucleoside reverse transcriptase inhibitors) | |||
| Delavirdine | CYP3A4, CYP2D6 | CYP3A4, CYP2C9, CYP2D6, CYP2C19 | |
| Efavirenz | CYP3A4, CYP2B6 | CYP3A4, CYP2C9, CYP2C19 | CYP3A4 |
| Nevirapine | CYP3A4 | CYP3A4 | |