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 μmol/L to 9.2 ± 1.9 μmol/L in male patients and from 32.5 ± 5.4 μmol/L to 6.3 ± 1.7 μmol/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. Clinical Pharmacology & Therapeutics (2003) 73 , 338–347; doi: 10.1016/S0009‐9236(02)17636‐3