Interactions between ARVs and antimalarials atovaquone and proguanil
23 August 2009. Related: Conference reports, PK and drug interactions, PK Workshop 10th 2009.
Simon Collins, HIV i-Base
Van Luin and colleagues from Nijmegen presented results showing significantly lower levels of the common antimalarials atovaquone and proguanil, commonly used together as prophylaxis, in HIV-positive patients on HAART compared to HIV-negative controls.
Seven-day PK results from HIV-positive patients already on established HAART including efavirenz (n=19), lopinavir/r (n=19) or atazanavir/r (n=19) were compared to levels in 20 HIV-negative volunteers following single-dose atovaquone/proguanil (250/150mg), administered with a fat standardised breakfast. Patients who were negative for CYP2C19 defective *2 and *3 alleles, the key enzyme for proguanil metabolism, were excluded from the proguanil comparisons.
PK parameters were significantly lower in HIV-positive patients (all p<0.05), and are detailed in Table 1. Efavirenz or lopinavir/r resulted in considerably reduced levels suggesting increased dosing may be required. Atazanavir/r considerably lowered proguanil compared to the HIV-negative group, but more modestly lowered atovaquone suggesting that this interaction may be managed with perfect adherence.
Table 1. Mean [range] atovaquone and proguanil levels
| HIV-negative | efavirenz | lopinavir/r | atazanavir/r | |
| Atovaquone | ||||
| AUC 0-t (h*mg/L) | 112.9 [43.3-250.1] | 35.3 [12.5-91.8] | 39.1 [6.3-137.0] | 75.3 [22.6-146 |
| Cmax (mg/L) | 2.0 [0.44-4.0] | 1.2 [0.39-2.8] | 1.3 [0.40-3.0] | 1.1 [0.54-2.2] |
| Proguanil (in patients without CYP2C19* or -*3) | ||||
| AUC 0-t (h*mg/L) | 1.3 [0.40-10.3] | 0.55 [0.12-1.8] | 0.42 [0.12-1.8] | 0.34 [0.10-0.63] |
Comment
An important problem with this study is the use of HIV-negative controls compared to HIV-positive patients, so the differences may have been due to differences in PK of antimalarials in HIV-positive people. These are interesting data, but the results need confirmation and cannot be regarded as definitive.
Reference:
Van Luin M et al. Drug interactions between atovaquone/proguanil and antiretroviral agents. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Oral poster O-19.