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 to 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 erythromycin breath test (ERMBT) to measure P450 3A activity on multiple occasions in twenty OG 37-325-treated renal transplant recipients. When stable dosing was achieved, there was a measured 6-fold variation in the ratio of 12-hr whole-blood parent compound trough concentration (ng/ml, HPLC) to daily OG 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 [OG 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 attain target blood levels. We also found that intrapatient variation in the [OG 37-325]/dose ratio observed over the course of the study correlated with changes in the ERMBT results (r = -0.67, P = 0.002). Inter- and intrapatient differences in [OG 37-325]/dose ratio were not predicted by patient age, serum cholesterol, blood hematocrit, or traditional liver chemistries. We conclude that P450 3A is generally rate limiting in the elimination of OG 37-325 in adult renal transplant recipients. Therefore, most drug interactions observed with CsA should also be expected with OG 37-325. We also conclude that intrapatient changes in OG 37-325 dosing requirements largely result from changes in P450 3A activity. The ERMBT may therefore provide useful information concerning patient compliance and may also serve as a useful guide to OG 37-325 dosing adjustments.
Department of Medicine, University of Michigan Medical Center, University of Michigan, Ann Arbor 48109-0108.
D K
DK
Turgeon
A B
AB
Leichtman
D S
DS
Blake
R L
RL
Schmouder
K S
KS
Lown
T M
TM
Annesley
P B
PB
Watkins
D000328:Adult; D001944:Breath Tests; D016572:Cyclosporine; D003524:Cyclosporins / Q000097:blood / Q000627:therapeutic use* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004917:Erythromycin; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use* / Q000633:toxicity*; D007674:Kidney Diseases / Q000601:surgery; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010349:Patient Compliance; D011237:Predictive Value of Tests; D012044:Regression Analysis
D003524:Cyclosporins; D007166:Immunosuppressive Agents; D004917:Erythromycin; C045571:cyclosporin G; D016572:Cyclosporine