Value of preemptive CYP2C19 genotyping in allogeneic stem cell transplant patients considered for pentamidine administration

Pneumocystis jirovecii prophylaxis is standard in allogeneic stem cell transplantation (alloSCT), sometimes with pentamidine at a low dose inhaled monthly. Human metabolism of pentamidine depends on cytochrome P450 2C19 (CYP2C19). The frequency of mutant CYP2C19 forms with decreased function (from 2% of Caucasians to 30% of Asians and 79% of certain Polynesians), together with common use of CYP2C19 inhibitors in the alloSCT process, creates risk for impaired pentamidine clearance resulting in toxicity ordinarily expected only with high doses given for active infection. We examined the charts of 32 consecutive pentamidine-prophylaxed alloSCT patients at our center. We assessed hospital charges for the management of toxicities unexplained at the time but likely attributable, in retrospect, to pentamidine. Twenty-eight percent experienced significant toxicities (incurring added charges of at least US$5000). Thirteen percent suffered major toxicity (incurring added charges of at least US$25000; median added charge $351701) and shorter survival (326 vs. 622d for all pentamidine recipients), including 6% who died of pentamidine toxicities [one proven postmortem to have a (non-functional) homozygous CYP2C19*2 mutation]. Charges for care attributable to pentamidine toxicity exceeded what preemptive genotyping would have cost by 73-fold. These findings encourage routine use of preemptive CYP2C19 genotyping in alloSCT patients considered for pentamidine.