CLINICAL PHARMACOKINETICS AND DISEASE PROCESSES

C1in. Pharmacokinet. 22 (3): 169-210. 1992 0312-5963/92/0003-0169/$21.00/0 © Adis International Limited. All rights reserved. CPKI

Clinical Pharmacokinetics of Antibiotics in Patients with Impaired Renal Function Wendy L. St Peter, Kimberly A. Redic-Kill and Charles E. Halstenson The Drug Evaluation Unit. Division of Nephrology, Hennepin County Medical Center and College of Pharmacy. University of Minnesota, Minneapolis. Minnesota

Contents 169 170 170

179

179 180 181 181

182 182 183 184 186 187 188 189 190

191 191 195

Summary

Summary I. Review of Pharmacokinetic Alterations in Renal Failure l.l Bioavailability and Absorption 1.2 Distribution 1.3 Metabolism 1.4 Renal Elimination 2. Factors Affecting Drug Removal by Haemodialysis 3. Dosage Adjustment in Renal Failure 4. Pharmacokinetics and Dosage Adjustments of Antibiotics 4. I Aminoglycosides 4.2 Antitubercular Agents 4.3 Carbapenems and Monobactams 4.4 Cephalosporins 4.5 Auoroquinolones 4.6 Glycopeptides 4.7 Macrolide Antibiotics 4.8 Penicillins 4.9 Tetracyclines 4.10 Miscellaneous 5. Discussion and Conclusions

Many antibiotics are eliminated renally and dosage adjustments are commonly made in patients with renal insufficiency. This is a critical review of antibiotic pharmacokinetics in patients with various degrees of renal function . Detailed information regarding pharmacokinetic alterations with specific antibiotics or antibiotic classes has been compiled and tabulated. From pharmacokinetic evidence. recommendations for dosage adjustments of antibiotics are supplied. The criteria used for assigning rating levels to specific pharmacokinetic articles as well as the grading system for dosage adjustments are outlined. In addition, a basic review of pharmacokinetic alterations in renal failure and factors affecting the removal of drugs by haemodialysis is included.

170

Many review articles on antibiotic administration in patients with various degrees of renal function have been published (Bennett et al. 1983b; Bernstein & Erk 1990; Fillastre & Singlas 1991 ; Gilbert & Bennett 1989; Keller et al. 1982; Matzke & Keane 1986; Reed & Sabatani 1986; Van Scoy & Wilson 1987); however, none has critically analysed the available pharmacokinetic data to determine the validity of published dosage recommendations. Relevant pharmacokinetic articles reviewing marketed antibiotics used frequently within the United States along with those that have had New Drug Applications submitted to the US Food and Drug Administration were identified with a search ofthe English language literature using MEDLINE (1966 to 1991), bibliographical reviews of textbooks, review articles and original research articles. The database was confined to pharmacokinetic trials in adults with normal renal function, patients with various degrees of renal function or patients with end-stage renal disease (ESRD) who were maintained on haemodialysis; and animal data were used where human data did not exist. Since pharmacokinetic trials in patients receiving peritoneal dialysis have recently been reviewed (Keller et al. 1990) we did not re-examine them. Using a methodology similar to that of the second American College of Chest Physicians Conference on Antithrombotic Therapy (Sackett 1989), each original research article or abstract was assigned a level (I to IV) based on the guidelines (table I) established from several references (Brazzell & Colburn 1986; Gibson 1985; Koup 1989; Smith 1986; Spilker 1984). The assigned level determined which pharmacokinetic data were tabulated in table II. Information extracted from each citation (when available) included the age and bodyweight of participants, apparent volume of distribution (Vd) using the steady-state (V55) or area (Varea) method in L/kg, total body clearance (CL) in ml/min/kg, terminal elimination rate (leeJ) in h- i and terminal elimination half-life (t'12I1) in hours, half-life during haemodialysis (t'12D) in hours, haemodialyser clearance (CLD) in ml/min, degree of plasma protein

Clin. Pharmacokinet. 22 (3) 1992

binding (PPB) and fraction of the systemically available drug excreted unchanged in the urine (fe) as well as citation dosage recommendations. When the pharmacokinetic values above were not computed, we calculated parameters if there were adequate raw data. Weighted mean pharmacokinetic values were calculated on the basis of the number of patients or volunteers falling into a specific creatinine clearance (CLcR) category. Renal function was categorised on the basis of measured or estimated CLcR, according to the following 4 categories: >50, 30 to 50, 10 to 30 and < 10 mlfmin (>3, 1.8 to 3, 0.6 to 1.8 and 50 mlfmin (3 L/h) does not define normal renal function, dosage adjustment with antibiotics is rarely advocated until CLcR falls below this level. Notable exceptions are aminoglycoside antibiotics and vancomycin where the dosage is usually individualised across the spectrum of renal function. Table II contains all compiled pharmacokinetic data arranged by drug class. Maintenance antibiotic dosage recommendations found in table II were based on mean pharmacokinetic parameters derived for each antibiotic in each CLcR category. The dosage recommendations for each antibiotic were rated (A, B or C) based on the strength of the supporting pharmacokinetic literature for all CLcR groups. To receive an A rating, there had to be level I supportive pharmacokinetic data in each CLcR category. The dosage recommendations must be interpreted with the knowledge that the majority of data were derived from pharmacokinetic trials that did not provide dosage simulations with known bacterial minimum inhibitory concentration (MIC) data (section 3). Information regarding administration after haemodialysis can also be found in table II. Relationships between CL or keJ and CLCR are outlined in table III.

1. Review of Pharmacokinetic Alterations in Renal Failure 1.1 Bioavailability and Absorption Bioavailability is a measure of extent of drug absorption into the systemic circulation after extravascular administration. There are only a few

Antibiotic Pharmacokinetics in Renal Failure

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Table I. Relationship between levels of evidence and grading recommendations for studies included in the analysis Level

General criteria

Haemodialysls criteria

I: Prospectively designed human pharmacokinetic trials

1. Subjects representative of otherwise healthy, normal individuals with stable renal function 2. ;;.6 participants in each CLcR category 3. Degree of renal insufficiency in patients should be characterised by measured CLcR obtained via appropriate urine and serum sampling 4. Study methodology should be appropriate, particularly with respect to: (a) dosage strategy and dosage form (b) sample collection and handling (c) analytical procedures (d) data analysis (e) statistical methods

1. Must meet level I general criteria where applicable 2. To determine interdialysis pharmacokinetics the drug should be given IV and the plasma concentration-time curve should be followed for ;;'1-2 x t~ before haemodialysis starts with sufficient samples to adequately characterise absorption (if PO) and distribution phases 3. To determine intradialysis pharmacokinetics, the drug should be given with time allowed for complete absorption and distribution and then dialysis started 4. Amount recovered In dialysate method or multiple AV pairs used to calculate dlalyser clearance; however, AV pairs method less desirable 5. Dialysis conditions should be stated (dialyser type, length of dialysis, blood flow rate, dialysate flow rate) 6. Sufficient blood samples should be taken after haemodialysis completed to assess postdialysis rebound

II: Prospectively designed pharmacokinetic human trials

1. Stable renal function 2. ;;.3 participants In each CLcR category 3. Measured or estimated CLcR 4. Pharmacokinetic parameters measured or calculated from other parameters 5. Study methodology may be incomplete

1. Must meet level II general criteria where applicable 2. Must meet level I haemodialysis criteria 2,

3,4,5

iii: Human trials

1. Does not meet level I or level II general criteria 2. Case studies 3. Retrospective studies 4. Abstracts

1. Does not meet level II haemodialysis criteria 2. Case studies 3. Retrospective studies 4. Abstracts

IV: Miscellaneous

1. Nonhuman data 2. Clinical experience of authors

1. Nonhuman data 2. Clinical experience of authors

Abbreviations: CLcR = creatinine clearance;

t~

= elimination half-life; IV = intravenous; PO = oral; AV = arteriovenous.

studies which specifically address the issue of drug bioavailability in patients with renal failure. Plaisance and colleagues (1990) found no difference in ciprofloxacin bioavailability in patients with renal failure. However, there are data to suggest that patients with uraemia exhibit delayed gastric emptying (McNamee et al. 1985) which may delay the appearance of some drugs in the systemic cir-

culation. Unfortunately, the latter authors did not mention whether any patients had diabetes-associated gastroparesis. Renal failure may affect the absorptive capacity of the small intestine. Craig and associates (1978) showed that D-xylose absorption is reduced by one-third and its appearance in the systemic circulation is delayed 2-fold in patients with uraemia.

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Table II. Pharmacokinetic parameters and dosage recommendations In various degrees of renal function and haemodialysis. In general, for 1g every 4h to 2g every 6h) Drug (metabolite)

v•• (L/kg) normal

ESRD

CL (ml/min/kg)

tv..s (h)

PPB (%)

normal

ClcR (ml/min)

normal ESRD

ESRD

>50

30-50

fa (%)

10-30