Are the pharmacokinetics of moxifloxacin and rifabutin altered in patients with cystic fibrosis?

Fråga: Are the pharmacokinetics of moxifloxacin and rifabutin altered in patients with cystic fibrosis?

Sammanfattning: We found no data on the pharmacokinetics of moxifloxacin or rifabutin in patients with cystic fibrosis, and the theoretical risk of altered elimination is not such that it warrants a deviation from standard doses. Nevertheless, an increased elimination of rifabutin cannot be excluded, and therapeutic drug monitoring of this drug is strongly recommended in this patient.

Svar: We have found no reports of altered moxifloxacin or rifabutin pharmacokinetics in cystic fibrosis patiens in Drugline, Medline or standard pharmacologic literature. However, there is evidence that the turnover of several other drugs is altered in cystic fibrosis. These changes involve both volume of distribution (due to reduced levels of plasma proteins and body fat) and clearance. Typically, drug clearance is increased and the mechanisms involve both enhanced metabolism (eg via cytochrome P450 (CYP) 2C8, N-acetyltransferase 1 (NAT1), sulfotransferase and, possibly, CYP1A2) and increased renal excretion (via alterations in GFR and tubular secretion) (1). Examples of drugs where the weight-adjusted metabolic clearance is substantially (+ 50 to 130 percent) increased in cystic fibrosis include cloxacillin, theophylline, ciprofloxacin, R-warfarin, furosemide, ibuprofen, sulfamethoxazole, paracetamol and lorazepam. Increases in renal clearance by 20 to 85 percent have been demonstrated for e.g. aminoglycosides, penicillins, ciprofloxacin, thrimetoprim and ceftazidime (1, 2). For the renally excreted penicillin dicloxacillin, a single small study demonstrated a dramatic 3-fold increase in clearance (3).

Moxifloxacin is not metabolized by cytochrome P450 enzymes, but undergoes glucuronidation (via UDP-glucuronosyltransferase 1A1) and sulfatation (via sulfotransferase 2A1) resulting in pharmacologically inactive conjugates (4, 5, 6). UGT1A1 is of small importance for the glucuronidation of the drugs whose metabolic clearance is known to increase in cystic fibrosis, and sulfotransferase 1E1 is thought to primarily account for the enhanced sulfatation (7, 8, 9, 10). Hence, there is no obvious reason to expect an increased metabolism of moxifloxacin. In addition, the fact that the drug is excreted in feces as well as urine, both unchanged and as metabolites, should reduce the importance of any single pathway. This notion gains some support from the fact that no moxifloxacin dose adjustments are required in patients with altered renal or hepatic function (4).

Rifabutin is extensively metabolized, mainly by CYP3A4 (which it also induces) and arylacetamide deacetylase (11, 12). It is excreted in urine and feces, primarily as metabolites with varying antibacterial activity (13). The CYP3A4 enzyme activity is not altered in cystic fibrosis and we have found no information on the activity of arylacetamide deacetylase (1). Although the renal function is of importance for the rifabutin dose requirements (15) and an increased renal excretion of rifabutin and its metabolites in cystic fibrosis cannot be excluded, there is insufficient evidence to recommend a dose increase from the start of treatment. This conclusion is corroborated by a recently published Cochrane review, recommending standard treatment regimes for nontuberculous mycobacteria lung infections in individuals with cystic fibrosis, due to a general lack of data in this patient group (14). Rey E, Treluyer JM, Pons G. Drug disposition in cystic fibrosis. Clin Pharmacokinet 1998;35(4):313-29 Touw DJ. Clinical pharmacokinetics of antimicrobial drugs in cystic fibrosis. Pharm World Sci 1998;20(4):149-60 Jusko WJ, Mosovich LL, Gerbracht LM, Mattar ME, Yaffe SJ. Enhanced renal excretion of dicloxacillin in patients with cystic fibrosis. Pediatrics 1975;56:1038-44 Avelox. Bayer. SPC (cited 2014-10-20) Tachibana M, Tanaka M, Masubuchi Y, Horie T. Acyl glucuronidation of fluoroquinolone antibiotics by the UDP-glucuronosyltransferase 1A subfamily in human liver microsomes. Drug Metab Dispos 2005;33:803-11 Senggunprai L, Yoshinari K, Yamazoe Y. Selective role of sulfotransferase 2A1 (SULT2A1) in the N-sulfoconjugation of quinolone drugs in humans. Drug Metab Dispos 2009;37(8):1711-7 Uchaipichat V, Suthisisang C, Miners JO. The glucuronidation of R- and S-lorazepam: human liver microsomal kinetics, UDP-glucuronosyltransferase enzyme selectivity, and inhibition by drugs. Drug Metab Dispos 2013;41(6):1273-84 Liston HL, Markowitz JS, DeVane CL. Drug glucuronidation in clinical psychopharmacology. J Clin Psychopharmacol 2001;21(5):500-15 Kiang TK, Ensom MH, Chang TK. UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacol Ther 2005;106:97-132 Falany CN, He D, Li L, Falany JL, Wilborn TW, Kocarek TA, Runge-Morris M. Regulation of hepatic sulfotransferase (SULT) 1E1 expression and effects of estrogenic activity in cystic fibrosis (CF). J Steroid Biochem Mo Biol 2009;114(1-2):113-9 Prasad B, Singh S. In vitro reaction phenotyping studies on rifamycins to explain the auto-induction of rifabutin metabolism. Int J Tuberc Lung Dis 2012;16(2):232-4 Nakajima A, Fukami T, Kobayashi Y, Watanabe A, Nakajima M, Yokoi T. Human arylacetamide deacetylase is responsible for deacetylation of rifamycins: rifampicin, rifabutin, and rifapentine. Biochem Pharmacol 2011;82(11):1747-56 Dollery C Sir, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone; 1999. pp R26-R32 Waters V, Ratjen F. Antibiotic treatment for nontuberculous mycobacteria lung infection in people with cystic fibrosis (Review). Cochrane Database Syst Rev 2012 Dec 12;12:CD010004. Doi: 10.1002/14651858. CD010004.pub2 Ansatipin. Produktresumé (SPC) (cited 2014-11-11)