PREDICTION OF INTERPATIENT AND INTRAPATIENT VARIATION IN OG-37-325 DOSING REQUIREMENTS BY THE ERYTHROMYCIN BREATH TEST - A PROSPECTIVE-STUDY IN RENAL-TRANSPLANT RECIPIENTS

OG 37-325 (nva-cyclosporine, cyclosporine G) is structurally similar t o cyclosporine A (CsA). We hypothesized that OG 37-325 may, therefore, be metabolized by P450 3A, an enzyme recently shown to metabolize CsA . To test this hypothesis, we employed the erythro mycin breath test ( ERMBT) to measure P450 3A activity on multiple occasions in twenty OG 37-325-treated renal transplant recipients. When stable dosing was ach ieved, there was a measured 6-fold variation in the ratio of 12-hr who le-blood parent compound trough concentration (ng/ml, HPLC) to daily O G 37-325 dose (mg/kg) ([OG 37-325]/dose). In support of our hypothesis , there was an inverse correlation between the ERMBT result and the [O G 37-325]/dose ratio (r=-0.71, P<0.001, n=20); that is, patients with higher P450 3A activity generally required higher OG 37-325 doses to a ttain target blood levels. We also found that intrapatient variation i n the [OG 37-325]/dose ratio observed over the course of the study cor related with changes in the ERMBT results (r=-0.67, P=0.002). Inter- a nd intrapatient differences in [OG 37-325]/dose ratio were not predict ed by patient age, serum cholesterol, blood hematocrit, or traditional liver chemistries. We conclude that P450 3A is generally rate limitin g in the elimination of OG 37-325 in adult renal transplant recipients . Therefore, most drug interactions observed with CsA should also be e xpected with OG 37-325. We also conclude that intrapatient changes in OG 37-325 dosing requirements largely result from changes in P450 3A a ctivity. The ERMBT may therefore provide useful information concerning patient compliance and may also serve as a useful guide to OG 37-325 dosing adjustments.