Clofazimine

Study objectives: Determine hemodialysis clearances of the second-line antitubercular drugs cycloserine (CS), ethionamide (ETA), para-aminosalicylate (PAS), and clofazimine (CFZ).

Design: Open-label, pharmacokinetic study

Setting: Outpatient long-term hemodialysis unit

Participants: Eight long-term hemodialysis patients

Interventions: Single oral doses of CS, 500 mg, ETA, 500 mg, PAS, 4,000 mg, and CFZ, 200 mg, were given 2 h (4 h for PAS) prior to hemodialysis (median blood flow rate, 400 mL/min; median dialysate flow rate, 600 mL/min; median hemodialysis time, 3.5 h).

Measurements and results: Arterial and venous serum samples were collected at the beginning and end of hemodialysis, and hourly during hemodialysis. Dialysate fluid was collected for the duration of hemodialysis. All samples were assayed for drug concentrations using validated high-performance liquid chromatography (for ETA and PAS), capillary electrophoresis (for CS), and colorimetry (for CFZ). Dialysate samples were analyzed for acetyl-PAS. Median recoveries of drug in dialysate were 56% (CS), 2.1% (ETA), 6.3% (PAS parent compound), and 0% (CFZ)of the doses administered. Acetyl-PAS was dialyzed to a greater extent than its parent compound. Median hemodialysis clearances calculated by dividing the amount recovered in dialysate by the serum area under the curve during dialysis were 189 (CS), 58 (ETA), 206 (PAS), and 0 (CFZ) mL/min.

Conclusions: ETA, CFZ, and PAS were not significantly dialyzed. CS is significantly removed by hemodialysis and should be dosed after hemodialysis. (CHEST 1999; 116:984-990)

Key words: hemodialysis, cycloserine, ethionamide, para-aminosalicylate, clofazimine, tuberculosis, pharmacokinetics

Abbreviations: AUC = area under the curve; CE = capillary electrophoresis; CFZ = clofazimine; ClHD = hemodialysis clearance; Cmax = maximal serum concentration; CS = cycloserine; CV = coefficient of variation; ER = extraction ratio; ETA = ethionamide; PAS = para-aminosalicylate; QC = quality control; TB = tuberculosis; Truax = time of maximal serum concentration;

Due to immunologic abnormalities associated with end-stage renal disease, patients receiving long-term hemodialysis are more susceptible to tuberculosis (TB) and other infections than the general population.[1] In the late 1970s and early 1980s, reports from the United States, England, Canada, and Japan demonstrated that TB is 10 to 15 times more common in long-term hemodialysis patients than the surrounding populations.[2-7] More recently, 9% of the total mortality from 1994 to 1997 at a dialysis center in Turkey was attributed to TB.[8] In 1995, 8% of dialysis centers across the United States reported patients with active TB,[9] including 20% of dialysis centers in New York State. Incidences of TB of 23.6% and 28%, respectively, were reported in hemodialysis patients in areas in Saudi Arabia and Turkey, which have an overall prevalence rate of 1% for TB.[10,11] The diagnosis of TB in patients with end-stage renal disease is often complicated by atypical clinical presentation, nonspecific symptoms that may be attributed to uremia, negative results of skin tests, and a higher occurrence of extrapulmonary TB compared to other patient populations.[1-5,7,12-15] Awareness of the increased incidence of TB and its atypical presentation in end-stage renal disease results in earlier diagnosis and treatment of TB and enhances patient outcomes.[10,11]

Drug-resistant TB is a global concern.[16] Second-line antitubercular agents such as cycloserine (CS), ethionamide (ETA), para-aminosalicylate (PAS), and clofazimine (CFZ) are used to treat drug-resistant TB.[17,18] The disposition of these agents in patients receiving hemodialysis is unknown. The present study examines the effect of hemodialysis using high-flux dialyzers on the removal of these antimycobacterial drugs from serum and reports drug recovery by dialysate collection.

MATERIALS AND METHODS

Subjects

Eight volunteers receiving long-term hemodialysis were recruited from the Rocky Mountain Kidney Center in Denver, CO, between March 1996 and November 1997. Eligible subjects were those between the ages of 18 and 75 years with end-stage renal disease requiring long-term hemodialysis. Potential subjects were excluded on the basis of any known allergies to antimycobacterial drugs or related agents, history of significant liver disease, results of baseline liver function tests (ie, ratio of serum alanine aminotransferase to serum aspartate aminotransferase, alkaline phosphatase level, or total bilirubin level) greater than three times the upper limit of normal, history or clinical evidence of heart failure, severe anemia (hematocrit, [is less than] 28%), or pregnancy/lactation. The Colorado Multiple Institutional Review Board approved the study protocol. Informed consent was obtained from each subject prior to participation in the study.

Hemodialysis Procedure

At the time of study participation, subjects received their usually prescribed hemodialysis regimens. Dialyzer type, blood, dialysate and ultrafiltrate flow rates, and duration of hemodialysis were not changed for study purposes. All of these parameters and the number of times the dialyzer had been previously used were recorded. The system used for all patients composed of a hemodialysis machine (Centrysystem3; Cobe Laboratories; Lakewood, CO) with a high-flux dialyzer (Fresenius Hemoflow; Fresenius USA, Inc; Walnut Creek, CA) and a single-pass dialysate flow.

Medications

Subjects were given single oral doses of CS (Seromycin; Dura Pharmaceuticals; San Diego, CA), 500 mg, ETA (Trecator-SC; Wyeth-Ayerst; Philadelphia, PA), 500 mg, CFZ (Lamprene; Novartis; East Hanover, NJ), 200 mg, and PAS (PASER granules; Jacobus Pharmaceutical Company, Inc; Princeton, NJ), 4,000 mg. The subjects were instructed to take the PAS with an acidic beverage such as fruit juice 4 h prior to a regularly scheduled hemodialysis session. The other medications were to be taken all at once 2 h later. The subjects were asked not to eat anything for 1 h before or after taking study medications. Subjects were contacted by telephone when medications were due and were reminded to take them according to the study protocol.

Sample Collection

Blood samples of 8 mL each to be analyzed for CS, ETA, CFZ, and PAS concentrations were taken from ports in the arterial and venous tubing of the dialyzer at the start of the hemodialysis session and then were taken hourly, with final samples taken as hemodialysis was discontinued. Samples were collected in plain red-top vacuum tubes, placed on ice, and centrifuged within 60 min of collection. Serum then was harvested into labeled polypropylene tubes and stored at -70 [degrees] C until assayed. Samples were frozen within 90 rain of collection. For the duration of the dialysis session, all dialysate/ultrafiltrate fluid leaving the system was collected in 20-L containers. When each container approached full, it was removed from the system and the collected volume was recorded. From each container, an 80-mL dialysate/ ultrafiltrate sample was collected and frozen promptly at -70 [degrees] C. The remainder of the fluid was discarded.

Sample Analysis

Serum samples were assayed for drug concentrations according to validated procedures at the Infectious Disease Pharmacokinetics Laboratory at National Jewish Medical and Research Center in Denver, CO.

CS

Serum analyses were performed using a validated capillary electrophoresis (CE) assay on a CE system (Model 270A-HT; Hewlett Packard; Wilmington, DE) with ultraviolet detection. The six-point serum standard curves for CS ranged from 2.0 to 50.0 [micro]g/mL. The absolute recovery of CS from serum was 92.3%, as determined by comparing peak height counts across four serum curves to an unextracted solvent curve. The within-day precision (coefficient of variation [CV] percentage) of validation quality control (QC) samples was 3.5 to 10.7% CV, and the overall validation precision was 5.7 to 12.3% CV. QC sample concentrations were 7.5, 15, and 30 [micro]g/mL. For one patient who had an obvious interference with the CE method, serum samples were analyzed using a colorimetric method. All dialysate samples were analyzed colorimetrically. The colorimetric method used a spectrophotometer (model DU-20; Beckman Instruments, Inc; Fullerton, CA), and its overall validation precision was 3.7 to 9.6% CV.

ETA

All ETA assays were performed using a validated high-performance liquid chromatography assay using a pump (model 510; Waters; Milford, MA) and a gradient controller with a solvent select valve (model 680; Waters), a fixed-volume autosampler (model 8875; Spectra Physics; San Jose, CA), an ultraviolet detector (model 486; Waters), a computer (Macintosh Iici; Apple Computers, Inc; Cupertino, CA), and a high-performance liquid chromatography data management system (Dynamax; Rainin; Woburn, MA). The six-point standard curves for the ETA assay ranged from 0.2 to 10 [micro]g/mL, with linearity extending well above this range. The absolute recovery of ETA from serum was 90.7% of CV, as determined by comparing peak height counts across four serum curves to an unextracted solvent curve. The within-day precision of validation QC samples was 0.4 to 6.4% CV, and the overall validation precision was 0.8 to 4.7% CV. QC sample concentrations were 0.5, 1.5, and 7.0 [micro]g/mL. The dialysate method was a modification of the serum method with similar recovery and reproducibility.

CFZ

Serum and dialysate samples were analyzed using a colorimetric method. The colorimetric method used a spectrophotometer (DU-20; Beckman Instruments, Inc), and its overall validation precision was 4.1 to 10.7% CV

PAS

All PAS assays were performed using the same equipment as the ETA assays, with the exception of the use of a fluorescence detector (model FL-750; McPherson; Chelmsford, MA) with a high-sensitivity attachment. The six-point standard curves for the PAS assays ranged from i to 100 [micro]g/mL, with linearity extending well above this range. The absolute recovery of PAS from serum was 90.6%, as determined by comparing peak height counts across four serum curves to an unextracted solvent curve. The within-day precision of validation QC samples was 0.7 to 7.1% CV, and the overall validation precision was 3.2 to 10.6% CV. QC sample concentrations were 15, 30, and 80 [micro]g/mL. The dialysate method was a modification of the serum method, with similar recovery and reproducibility. After a prominent peak on the PAS chromatograms was identified as acetyl-PAS, a standard curve for acetyl-PAS in dialysate was made in the same manner as the PAS curve in dialysate. This was assayed along with a representative dialysate sample from each subject and was used to estimate the recovery of acetyl-PAS.

For all four drugs, concentrations in dialysate were often too low to be quantified, therefore, samples were concentrated 10-fold by lyophilizing 10-mL aliquots of the dialysate and reconstituting the samples to a volume of 1.0 mL. These assay results were divided by a factor of 10 to determine the dialysate concentrations.

Hemodialysis Clearance Determination

The dialyzer extraction ratio (ER), an indicator of the dialyzer's capability of removing drug, was calculated using serum drug concentrations as follows[19,20]:

ER = (As - Vs)/As

where As is arterial serum concentration and Vs' is venous serum concentration.

Previously published equations for calculating hemodialysis clearance (ClHD) were used[20,21]

(1) ClHDb = Qb [multiplied by] {(As - Vs)/As}

(2) ClHDs = Qb [multiplied by] (1 - Hct) [multiplied by] {(As - Vs)/As}

(3) ClHD = R/AUCs

(4) ClHD = Qd [multiplied by] {AUCd/AUCs}

where ClHDb is ClHD from blood, ClHDs is ClHD from serum, Qb is blood flow rate, Hct is hematocrit, R is the total amount of drug recovered in dialysate, AUCs is area under the curve of serum concentration vs time during hemodialysis, Qd is dialysate flow rate, and AUCd is area under the curve of dialysate concentration vs time.

The ER calculation and equations 1 and 2 were applied to samples collected 1 and 2 h into hemodialysis and at the end of hemodialysis. The median of the three values for each subject was used to determine a median value for the group. Calculations using recovery of drugs in dialysate (given in equations 3 and 4) are preferred to those based on the ER (given in equations 1 and 2).[20,21]

Calculations for AUC were made using the linear trapezoidal rule programmed into computer spreadsheets (Excel 97; Microsoft; Redmond, WA). Drug recovery in dialysate was calculated by multiplying the concentration of each dialysate sample by the total volume of the corresponding collection. Drug recovery as a percentage of the dose administered was determined by dividing the total amount of drug recovered in dialysate by the administered dose. Acetyl-PAS recovery expressed as PAS equivalents was used to calculate the percent of dose recovery. No corrections for expected bioavailability of the four drugs were made because bioavailability of the drugs in this patient population has not been studied.

Statistical Analysis

All statistical analyses were performed using computer software (JMP, version 3.2; SAS Institute; Cary, NC). Means with standard deviations and medians with ranges were determined for patient demographics and hemodialysis procedure characteristics as well as dialyzer ERs and clearance calculations.

RESULTS

Patient demographics and hemodialysis characteristics are summarized in Table 1. It is unlikely that the subjects had significant residual renal function because most of them had been receiving long-term hemodialysis for at least 12 months.

(*) Values given as median (range).

([dagger]) Includes day of study.

Although subjects were instructed to take CS, ETA, and CFZ 2 h prior to hemodialysis, the median time from dosing to the start of dialysis was 2.8 h (range, 1.9 to 3.9 h). These drugs typically reach their maximal serum concentrations (Cmax) 1 to 4 h (time to Cmax [Truax]) after oral administration, except for CFZ, which may be absorbed over as long as 12 h.22 Subjects were instructed to take the PAS dose 4 h prior to hemodialysis. The median time from dosing to the start of dialysis was 3.3 h (range, 2.5 to 5.9 h). The delayed-release formulation of PAS typically used reaches its Cmax 4 to 8 h after oral administration.[22] The apparent Cmax and Tmax for each drug studied along with normal values[22-26] are summarized in Table 2. The apparent Cmax was observed with the second or later samples in two subjects receiving ETA, three receiving PAS, and four receiving CFZ; indicating that absorption was not complete prior to initiating hemodialysis in these subjects. One subject was excluded from the CS hemodialysis clearance calculations, three from the PAS, and two from the CFZ because nondetectable or only trace amounts were found in the serum samples of these subjects.

(*) Values given at median (range) or mean [+ or -] SD unless otherwise indicated.

([dagger]) Cmax and Truax observed at steady state (from reference 22).

([double dagger]) Cmax observed after single 500-mg dose (from reference 23).

([sections]) Average Cmax observed after single 500-mg dose (from reference 24).

([parallel]) Median and range of Cmax observed after single 4000-mg dose (from reference 25).

([paragraph]) Average Cmax observed after single 200-mg dose (from reference 26).

Calculated dialyzer ERs, dialysis clearances, and drug recoveries in dialysate are summarized in Table 3. Due to the relatively small numbers of patients and a few outlying results, median values with ranges are presented. Estimated recoveries of acetyl-PAS are presented in Table 4. These results are expressed as the amount, in milligrams, of PAS equivalents recovered as a percentage of the PAS dose.

Table 3--Dialyzer ERs, hemodialysis clearances, and recoveries in dialysate(*)

(*) Values given as median (range).

([dagger]) Percentage of dose recovered as PAS parent compound.

Table 4--Estimated Recovery of PAS and acetyl-PAS (as PAS equivalents)(*)

(*) Values expressed as a percentage of the 4,000-mg dose.

([dagger]) Subject excluded from hemodialysis clearance calculations due to nondetectable or trace serum PAS concentrations.

DISCUSSION

Advantages and limitations of different hemodialysis clearance calculations are reviewed elsewhere.[20,27] Briefly, calculations based on dialysate recovery, such as those given in equations 3 and 4, are more accurate than those based on the ER, given in equations 1 and 2. Equation 1 is internally inconsistent in that it combines the whole-blood flow rate and serum ER and contains assumptions regarding serum/red cell equilibrium. Equation 2 uses the hematocrit as a factor to estimate serum flow, making the equation internally consistent. Equations 1 and 2 are affected by ultrafiltration.

CS

CS was significantly removed, with a median recovery in dialysate of 56% of the close administered. Because CS is primarily renally excreted, it may accumulate in renal failure, predisposing the patient to CNS toxicities.[28] We recommend that CS be used in its normal dose of 250 to 500 mg, but that it be given only three times a week after dialysis. This should avoid premature removal of CS during dialysis and accumulation between dialysis sessions.

ETA

Drug recovery of ETA, 2.1% of the dose, in dialysate was lower than expected based on hemodialysis clearances calculated from the ER. Drug adherence to the dialysis membrane may have occurred. However, ETA is rapidly metabolized by the liver, with a serum elimination half-life of 2 to 3 h.[28] It appears that hemodialysis does not effectively compete with metabolism for elimination of ETA from the body, which is the more likely explanation for the discrepancy between the observed ER and drug recovery. Dosage adjustment of ETA for renal failure or hemodialysis does not appear to be warranted.

PAS

PAS is normally rapidly metabolized in the GI tract and liver with an elimination half-life of 0.6 to 2.0 h.[26] Traditionally, PAS has been avoided in renal failure due to concern regarding accumulation of its inactive acetyl-PAS metabolite, which is eliminated renally.[29] There is also concern regarding recommendations that salicylates be avoided in renal failure because of their potential to exacerbate GI symptoms and platelet dysfunction associated with uremia.[30] Although PAS has rarely been associated with peptic ulcers and gastric bleeding,[31] PAS does not appear to have the antiplatelet effects associated with aspirin. Few reports are available regarding experience with PAS in patients with renal failure. Case reports involving five patients indicate that PAS has been used in patients with renal failure in doses ranging from 2 to 6 g after dialysis to 4.5 to 12 g/d. The dosage forms have not been indicated.[4,6,32,33] The patient who received 12 g/d experienced upper GI bleeding attributed to drug-induced gastritis.[4]

Our results suggest that hemodialysis is capable of removing PAS and acetyl-PAS. The chromatograms of PAS dialysate specimens displayed a large peak which we confirmed to be acetyl-PAS. Comparing the heights of these peaks to an acetyl-PAS standard curve allowed us to estimate recovery of acetyl-PAS in dialysate. In all subjects, including those that had only nondetectable or trace levels of PAS in serum, acetyl-PAS was detected in dialysate. Overall, recovery of acetyl-PAS was greater than that of its parent compound, confirming that metabolism remains the primary mode of elimination. The extent of absorption of the delayed-release PAS formulation is unknown. The low recoveries we observed may reflect incomplete absorption rather than low clearance by dialysis. The wide variation in recoveries of the parent and metabolite likely reflects variations in drug release from the delayed-release PAS formulation and in drug absorption among the individual subjects.

If PAS is used in a long-term hemodialysis patient, supplemental dosing to account for dialysis removal does not appear warranted. Due to the fact that acetyl-PAS is dialyzable, we suggest that PAS may be used in its usual dose of 4,000 mg twice daily, as is currently done for patients with normal renal function.[34]

CFZ

Extensive dialyzability of CFZ was not expected due to this drug's relatively large molecular size, lipophilicity, and wide deposition into tissues.[28] Because CFZ dialysate concentrations were nondectable or at trace levels for all subjects, the results of calculations using equations 3 and 4 are zero.

Although protein binding affects the dialyzability of drugs, it does not appear that protein binding characteristics of the drugs studied contributed significantly to the results. ETA and CS are not significantly protein bound.[22] The extent of protein binding of CFZ is unknown, however, properties of CFZ described above may explain the observation that it was not dialyzable as well as any protein binding that may have occurred. PAS is 50 to 73% protein bound.[22] This degree of protein binding is generally not considered clinically significant, however, this degree of protein binding could create a ceiling for the amount of drug that could be recovered in dialysate. The total recovery of PAS, as parent and metabolite, observed (6 to 47%) is consistent with the expected degree of protein binding.

As part of their prescribed dialysis regimens, five subjects used one model of dialyzer (model F80B; Fresenius USA, Inc; Walnut Creek, CA), and three subjects used another one (model F50B; Fresenius). These are both polysulfone dialyzers with surface areas of 1.8 [m.sup.2] and 1.0 m, respectively.[2] Manufacturer product information indicates that the F50B has lower clearances of urea, creatinine, phosphate, and vitamin B-12 than the F80B. For CS and ETA, observed hemodialysis clearances tended to be lower for subjects using the F50B than for subjects using the F80B dialyzer. The differences were not statistically significant, however, this study did not have the statistical power to detect such a difference.

Although somewhat problematic, using the oral dosage forms of CS, ETA, PAS, and CFZ that are available for routine clinical use may have enhanced applicability of the results. Administering study medications IV would have avoided problems associated with prolonged or incomplete absorption and facilitated complete distribution prior to starting dialysis. Injectable dosage forms of CS, ETA, CFZ, and PAS are not, however, available.

In some cases, drug absorption was not complete at the start of hemodialysis. If serum concentrations were higher during hemodialysis, drug recoveries and AUCs may have been higher. Hemodialysis clearances calculated from the AUCs should, however, still be valid because the AUCs during dialysis were used only in combination with corresponding dialysate concentrations.

We were unable to determine drug clearances between hemodialysis sessions or postdialysis rebound in drug concentrations due to logistical constraints. These limitations do not alter our conclusions, which are based primarily on the observed recoveries of drug in dialysate.

Administration of study medications was not directly monitored. A few subjects did not have measurable serum concentrations of some of their study medications. It is possible that these subjects did not take all the medications as instructed. Additionally, some individuals may have absorption difficulties. In the five subjects with measurable PAS concentrations, the median observed Cmax was 8.8 mg/L compared to 15.3 mg/L previously observed in healthy volunteers after a single 4,000-mg dose of PAS granules.[25]

The data in Table 2 suggest that ETA absorption is delayed in long-term hemodialysis patients. However, samples were not taken early enough to assess the Cmax for this drug appropriately. The observed Cmax levels for CS and CFZ are close to that expected after administration of a single dose.

CONCLUSION

CS is significantly dialyzed, with 56% of a 500-mg dose recovered in dialysate. CS may be given in its usual dose three times a week after dialysis. During hemodialysis, hepatic metabolism remains the primary route of elimination for ETA and PAS. ETA may be given in its usual dose of 250 to 500 mg twice daily. PAS may be given at a dose of 4000 mg twice daily. CFZ does not appear to be dialyzed and should be administered in its usual dose of 100 to 200 mg daily. Administration of all four drugs after dialysis on dialysis days may be advised in order to avoid premature removal of CS and to facilitate directly observed therapy.

ACKNOWLEDGMENT: The efforts of the staff of the Rocky Mountain Kidney Center are greatly appreciated.

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[16] Pablos-Mendez A, Raviglione MC, Laszlo A, et al. Global surveillance for antituberculosis-drug resistnace 1994-1997. N Engl J Med 1994; 338:1641-1649

[17] Iseman MD. Treatment of multi-drug resistant tuberculosis. N Engl J Med 1993; 329:784-791

[18] American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994; 149:1359-1374

[19] Lee CS, Marbury TC, Benet LZ. Clearance calculations in hemodialysis: application to blood, plasma, and dialysate measurements for ethambutol. J Pharmacokinet Biopharm 1980; 8:69-81

[20] Gibson TP. Problems in designing hemodialysis drug studies. Pharmacotherapy 1985; 5:23-29

[21] Barbhaiya RH, Knupp CA, Forgue ST, et al. Pharmacokinetics of cefepime in subjects with renal insufficiency. Clin Pharmacol Ther 1990; 48:268-276

[22] Peloquin CA. Using therapeutic drug monitoring to dose the antimycobacterial drugs. Clin Chest Med 1997; 18:79-87

[23] Zitkova L, Tousek J. Pharmacokinetics of cycloserine and terizidone. Chemotherapy 1974; 20:18-28

[24] Peloquin CA, James GT, McCarthy E, et al. Phramacokinetic evaluation of ethionamide suppositories. Pharmacotherapy 1991; 11:359-363

[25] Peloquin CA, Henshaw TL, Huitt GA, et al. Pharmacokinetic evaluation of para-aminosalicylic acid granules. Pharmacotherapy 1994; 14:40-46

[26] Garrelts JC. Clofazimine: a review of its use in leprosy and Mycobacterium avium complex infection. DICP Ann Pharmacother 1991; 25:525-531

[27] Matzke GR, Millikin SP. Influence of renal function and dialysis on drug disposition. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied pharmacokinetics: principles of therapeutic drug monitoring. Vancouver, WA: Applied Therapeutics, 1992; 8.1-8.49

[28] Peloquin CA. Antituberculosis drugs: pharmacokinetics. In: Heifets LB, ed. Drug susceptibilities in the chemotherapy of mycobacterial infections. Boca Raton, FL: CRC Press, 1991; 59-88

[29] Jacobus Pharmaceutical Company. Prescribing information for PASER[R] granules. Princeton, NJ: Jacobus Pharmaceutical Company, 1996

[30] Shuler C, Golper TA, Bennet WM. Prescribing drugs in renal disease. In: Brenner BM, ed. Brenner and Rector's the kidney. 5th ed. Philadelphia, PA: WB Saunders, 1996:26532702

[31] McEvoy GK. AHFS drug information. Bethesda, MD: American Society of Health-System Pharmacists, 1998:444-446

[32] Ogg CS, Toseland PA, Cameron JS. Pulmonary tuberculosis in patient on intermittent hemodialysis. BMJ 1968; 2:283-284

[33] Smith FW, Catto GRD, MacLeod M. Treatment of pulmonary tuberculosis in a patient on maintenance hemodialysis. Postgrad Med J 1974; 50:478-481

[34] Peloquin CA, Berning SE, Huitt GA, et al. Once-daily and twice-daily dosing of p-aminosalicylic acid (PAS) granules Am J Respir Crit Care Med 1999; 159:932-934

(*) From the Infectious Disease Pharmaeokineties Laboratory (Drs. Malone and Peloquin, and Mr. Childs), National Jewish Medical and Research Center, Denver, CO; and the School of Pharmacy (Dr. Fish) and the School of Medicine (Dr. Spiegel), University of Colorado Health Sciences Center, Denver, CO.

This research was funded by the Potts Memorial Foundation, the TB Foundation of Virginia, and National Institutes of Health grant 1RO1 AI37845.

Manuscript received February 19, 1999; revision accepted May 12, 1999.

Correspondence to: Charles A. Peloquin, PharmD, Infectious Disease Pharmacokinetics Laboratory, National Jewish Medical and Research Center, 1400 Jackson St, Denver, CO 80206; e-mail: Peloquinc@njc.org3

COPYRIGHT 1999 American College of Chest Physicians
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