Impact on carnitine homeostasis of short-term treatment with the pivalate prodrug cefditoren pivoxil.

Background: Pivalate-generating prodrugs have been suggested to cause clinically significant hypocarnitinemia. To evaluate the effect of pivalate prodrug treatment on carnitine homeostasis, we administered a pivalate prodrug, cefditoren pivoxil, to healthy subjects and performed carnitine balance studies.

Methods: Cefditoren pivoxil was administered in one of two dosing regimens (200 mg cefditoren twice daily for 10 days or 400 mg cefditoren twice daily for 14 days) to gender-balanced groups of 15 subjects. Plasma and urine concentrations of carnitine, acetylcarnitine, pivaloylcarnitine, and total carnitine were quantified before, during, and after treatment.

Results: Plasma carnitine concentrations fell during cefditoren pivoxil dosing. The nadir in carnitine concentration was dependent on the dose of cefditoren and subject gender (decrease from 44.8 +/- 10.9 micromol/L to 9.2 +/- 1.9 micromol/L in male patients and from 32.5 +/- 5.4 micromol/L to 6.3 +/- 1.7 micromol/L in female patients after 14 days of 400 mg cefditoren twice daily). Urinary elimination of pivaloylcarnitine resulted in a marked increase in total carnitine excretion, as well as net losses of total carnitine of approximately 4.6 mmol with the 200-mg, 10-day regimen and up to 14.9 mmol with the 400-mg, 14-day regimen. Pivaloylcarnitine was the dominant form of excreted pivalate.

Discussion: Short-term administration of cefditoren pivoxil results in hypocarnitinemia and increased net losses of total carnitine. It is estimated that net carnitine losses were only 10% of body stores, even with the highest dose regimen tested. Losses of this magnitude would not be anticipated to result in adverse clinical effects.