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Biomedical subjects

C A Peloquin

Publications and source records attributed to C A Peloquin.

At least 37 records · Page 2Linked to original sources
PubMed1999

Therapeutic drug monitoring in patients with cystic fibrosis and mycobacterial disease.

Cystic fibrosis (CF) patients require higher dosages of many antibiotics. The relapse of tuberculosis in one CF patient, and the repeated growth of Mycobacterium avium-intracellulare in another, despite conventional therapy, raised the question of whether the serum levels of the antimycobacterial drugs were adequate. Antimycobacterial drug serum concentrations were assayed in 10 CF patients with pulmonary mycobacterial disease. Serum levels below the proposed target range were seen 2 h after drug intake in the initial four patients treated: for rifampicin in 2/3, ethambutol in 3/4 and for clarithromycin in 2/3 patients, despite standard dosages. Reassays after dose adjustment and assays in six other patients showed that adequate levels were not achieved 4 h after clarithromycin in 3/5, ethambutol in 1/5, ciproflaxacin in 1/2 and ofloxacin in 2/2 patients. The patient with relapse of tuberculosis and the patient with continuous growth of M. avium-intracellulare improved and became culture negative after dose adjustment. Low drug serum levels is one reason for therapy failure in cystic fibrosis patients with mycobacterial disease. Therapeutic drug monitoring is recommended.

Adolescent↗
PubMed1999

Pharmacokinetics of ethambutol under fasting conditions, with food, and with antacids.

Ethambutol (EMB) is the most frequent "fourth drug" used for the empiric treatment of Mycobacterium tuberculosis and a frequently used drug for infections caused by Mycobacterium avium complex. The pharmacokinetics of EMB in serum were studied with 14 healthy males and females in a randomized, four-period crossover study. Subjects ingested single doses of EMB of 25 mg/kg of body weight under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. Serum was collected for 48 h and assayed by gas chromatography-mass spectrometry. Data were analyzed by noncompartmental methods and by a two-compartment pharmacokinetic model with zero-order absorption and first-order elimination. Both fasting conditions produced similar results: a mean (+/- standard deviation) EMB maximum concentration of drug in serum (Cmax) of 4.5 +/- 1.0 micrograms/ml, time to maximum concentration of drug in serum (Tmax) of 2.5 +/- 0.9 h, and area under the concentration-time curve from 0 h to infinity (AUC0-infinity) of 28.9 +/- 4.7 micrograms.h/ml. In the presence of antacids, subjects had a mean Cmax of 3.3 +/- 0.5 micrograms/ml, Tmax of 2.9 +/- 1.2 h, and AUC0-infinity of 27.5 +/- 5.9 micrograms.h/ml. In the presence of the Food and Drug Administration high-fat meal, subjects had a mean Cmax of 3.8 +/- 0.8 micrograms/ml, Tmax of 3.2 +/- 1.3 h, and AUC0-infinity of 29.6 +/- 4.7 micrograms.h/ml. These reductions in Cmax, delays in Tmax, and modest reductions in AUC0-infinity can be avoided by giving EMB on an empty stomach whenever possible.

Adult↗
PubMed1999

Lack of effect of zafirlukast on the pharmacokinetics of azithromycin, clarithromycin, and 14-hydroxyclarithromycin in healthy volunteers.

This randomized, open-label, crossover study was conducted to investigate whether the coadministration of zafirlukast would affect the pharmacokinetics of azithromycin, clarithromycin, or 14-hydroxyclarithromycin (14-OHC). Twelve healthy subjects (six males and six females) received single 500-mg doses of azithromycin and clarithromycin with and without zafirlukast given to a steady-state concentration. Blood was collected prior to all macrolide doses and for 3 and 10 days after each clarithromycin and azithromycin dose, respectively. Serum was assayed for azithromycin, clarithromycin, and 14-OHC concentrations by validated high-performance liquid chromatography assay systems. Data analyses were done by noncompartmental and nonparametric methods. Analysis of the patients indicated that the addition of steady-state concentrations of zafirlukast did not significantly alter the pharmacokinetic parameters of or overall exposure (based on the area under the concentration-time curve) to azithromycin, clarithromycin, and 14-OHC. While zafirlukast is a known inhibitor of CYP3A4, it does not appear to exert a clinically or statistically significant pharmacokinetic effect on azithromycin, clarithromycin, or 14-OHC.

Adult↗
PubMed1999

Once-daily and twice-daily dosing of p-aminosalicylic acid granules.

The study objective was to determine the minimum frequency of dosing for standard 4-g doses of p-aminosalicylic acid (PAS) granules. Two sequential six-patient pharmacokinetic studies are described, followed by clinical data from 40 subsequent patients. All patients had multidrug-resistant tuberculosis (MDR-TB). Serum was collected at two to three time points after dosing, and assayed by a validated high performance liquid chromatography (HPLC) assay. Data were analyzed using noncompartmental methods. In six patients, twice-daily dosing produced median serum concentrations at 4, 8, and 12 h post-dose of 25.8, 23.2, and 16.4 microgram/ml. In six patients, once-daily dosing produced median serum concentrations at 6, 12, and 24 h post-dose of 23.4, 3.7, and 0 microgram/ml. In 40 patients, twice-daily dosing produced median serum concentrations at 4 to 8 and 9 to 12 h post-dose of 24.8 and 20.6 microgram/ml. Unlike once-daily dosing, twice-daily PAS maintained serum concentrations in excess of 1 microgram/ml, the typical minimal inhibitory concentration against Mycobacterium tuberculosis, for the entire dosing interval. We now use twice-daily PAS granules for our patients with MDR-TB.

Adolescent↗
PubMed1999

The effect of hemodialysis on isoniazid, rifampin, pyrazinamide, and ethambutol.

This study examines hemodialysis clearances of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB). Seven chronic hemodialysis patients were studied. Six were given single oral doses (INH 300 mg, RIF 600 mg, PZA 1000 mg, and EMB 25 mg/kg) 2 h before hemodialysis (Cobe Centrysystem 3 hemodialysis machine; Fresenius F80B dialyzer; median blood flow rate 400 ml/min; dialysate flow rate 600 ml/min; median hemodialysis time 3.5 h). The seventh subject, being treated for tuberculosis (TB), was studied with his usual regimen. Arterial and venous serum samples were collected at the beginning and end of hemodialysis, and hourly during hemodialysis. Dialysate was collected for the duration of hemodialysis. All samples were assayed for drug concentrations using high-performance liquid chromatography (HPLC) (INH, RIF) and gas chromatography/mass spectrometry (GC/MS) (PZA, EMB) methods. Median recoveries of drug in dialysate were 9% (INH), 4% (RIF), 45% (PZA), and 2% (EMB) of the doses administered. Median hemodialysis clearances calculated by dividing the amount recovered in dialysate by the serum area under the curve during hemodialysis were 124 (INH), 40 (RIF), 270 (PZA), and 46 (EMB) ml/min. INH, RIF, and EMB were not significantly removed by hemodialysis. PZA is significantly dialyzed and should be dosed after hemodialysis.

Adult↗
PubMed1999

Multidrug-resistant tuberculosis meningitis: clinical problems and concentrations of second-line antituberculous medications.

OBJECTIVE: [corrected] To describe a case of culture-proven multidrug-resistant tuberculous (MDR-TB) meningitis, in which the patient survived long enough for clinicians to adjust antituberculous therapy to second-line therapeutic agents. DESIGN: Case report. SETTING: Tertiary care hospital. PATIENT: Twenty-one-month-old girl with MDR-TB meningitis. INTERVENTIONS: Initial standard treatment failed. Subsequent treatment with second-line therapeutic agents including ciprofloxacin, cycloserine, ethambutol, ethionamide, and rifabutin were given for approximately two years. Concentrations of these drugs were measured in serum and cerebrospinal fluid in the presence and absence of meningeal inflammation. MAIN OUTCOME MEASURES/RESULTS: The patient survived for approximately two years after initiation of second-line anti-TB therapy. During this treatment, she developed a ventriculo-peritoneal shunt tunnel tract infection secondary to MDR-TB. CONCLUSIONS: All TB meningitis isolates for which the source case antibiotic susceptibility pattern is not known should be cultured and susceptibility tested using rapid broth techniques. Measurement and subsequent adjustment of therapeutic drug concentrations may optimize therapy with second-line anti-TB drugs in TB meningitis. Better pediatric formulations and pharmacokinetic data for second-line and anti-TB therapeutic agents are needed.

Antitubercular Agents↗
PubMed1999

Pharmacokinetics of rifampin under fasting conditions, with food, and with antacids.

STUDY OBJECTIVES: Determine the intrasubject and intersubject variability in, and the effects of food or antacids on, the pharmacokinetics of rifampin (RIF). DESIGN: Randomized, four-period crossover phase I study. SUBJECTS: Fourteen healthy male and female volunteers. INTERVENTIONS: Subjects ingested single doses of RIF, 600 mg, under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. They also received standard doses of isoniazid, pyrazinamide, and ethambutol. MEASUREMENTS AND MAIN RESULTS: Serum was collected for 48 h and assayed by high-pressure liquid chromatography. Data were analyzed using noncompartmental methods and a compartmental analysis using nonparametric expectation maximization. Both fasting conditions produced similar results: a mean RIF maximal serum concentration (Cmax) of 10.54+/-3.18 microg/mL, the time at which it occurred (Tmax) of 2.42+/-1.32 h, and the area under the curve from time zero to infinity (AUC0-infinity) of 57.15+/-13.41 microg x h/mL. These findings are similar to those reported previously. Antacids did not alter these parameters (Cmax of 10.89+/-5.22 microg/mL, Tmax of 2.36+/-1.28 h, and AUC0-infinity of 58.37+/-18.49 microg x h/mL). In contrast, the Food and Drug Administration high-fat meal reduced RIF Cmax by 36% (7.27+/-2.29 microg/mL), nearly doubled Tmax (4.43+/-1.09 h), but reduced AUC0-infinity by only 6% (55.20+/-14.48 microg x h/mL). CONCLUSIONS: These changes in Cmax, Tmax, and AUC0-infinity can be avoided by giving RIF on an empty stomach whenever possible.

Adult↗
PubMed1999

The effect of hemodialysis on cycloserine, ethionamide, para-aminosalicylate, and 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.

Adolescent↗
PubMed1999

Potential interaction between itraconazole and clarithromycin.

Three patients negative for human immunodeficiency virus infection were admitted for pulmonary Mycobacterium avium complex (MAC) and aspergillosis infections. They were treated with different drug combinations, but all regimens included clarithromycin for MAC and itraconazole for aspergillosis. All patients experienced an increase in clarithromycin concentrations and clarithromycin: 14-OH-clarithromycin ratio compared with expected range values. They had no clinical side effects. The time course suggested a possible interaction between clarithromycin and itraconazole, presumably through itraconazole's effects on cytochrome P450 3A4 activity. A bidirectional interaction cannot be ruled out. The data suggest that, when necessary, these two drugs can be administered together safely. Further investigation is necessary to determine the extent and clinical consequences of coadministration in humans.

Adult↗
PubMed1999

Clarithromycin pharmacokinetics in the desert tortoise (Gopherus agassizii).

Clarithromycin is a new, safe orally administered macrolide antibiotic active against Mycoplasma sp. in humans. Single-dose and multidose pharmacokinetic parameters were determined for clarithromycin in wild-caught desert tortoises (Gopherus agassizii) seropositive for M. agassizii. Clarithromycin blood levels were measured in three tortoises for up to 72 hr after a single oral dose of 7.5 mg/kg. In a second group of six tortoises, levels were measured after a dose of 15 mg/kg. Noncompartmental iterative two-stage Bayesian and nonparametric expectation maximization pharmacokinetic parameters were determined for each animal assuming first order rate constants. At 15 mg/kg, the maximum concentration was 1.37 microg/ml, the time to maximum concentration was 8.0 hr, and a plasma half-life of 11.69 hr was derived from the latter method. The absorption constant was 0.08/hr, the absorption half-life was 8.47 hr, and the weight-normalized volume of distribution was 5.30 L/kg. Predictions derived by the latter method suggested a dosage of 15 mg/kg p.o. every 24 hr to achieve maximal blood levels of > or =1 microg/ml for multiple dosing. However, results from a preliminary multidose study with three tortoises indicate that the drug is accumulated; therefore, the predicted dose may be closer to 15 mg/kg p.o. every 2-3 days to maintain blood levels of 2-7.5 microg/ml. (For n = 3, 2-point linear regression median estimates for the apparent elimination rate constant (K) and half-life are 0.0227/hr and 30.52 hr, respectively.) This multidose accumulation reflects a slower apparent elimination than that predicted in the eight single-dose tortoises (i.e., K = 0.0593/hr, t1/2 = 11.69 hr). This study highlights a potential pitfall of depending solely on single-dose studies and the potential value of oral administration in reptiles.

Administration, Oral↗
PubMed1999

Pharmacokinetics of isoniazid under fasting conditions, with food, and with antacids.

STUDY OBJECTIVES: To determine the intra- and intersubject variability in and the effects of food or antacids on the pharmacokinetics of isoniazid (INH). DESIGN: Randomized, four-period cross-over Phase I study in 14 healthy male and female volunteers. Subjects ingested single doses of INH 300 mg under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. They also received standard doses of rifampin, pyrazinamide, and ethambutol. RESULTS: Serum was collected for 48 hours, and assayed by high performance liquid chromatography (HPLC). Data were analyzed using noncompartmental methods and a compartmental analysis using nonparametric expectation maximization. Both fasting conditions produced similar results: a mean INH Cmax of 5.53 +/- 2.92 microg/ml, Tmax of 1.02 +/- 1.10 hours, and AUC0-infinity of 20.16 +/- 12.45 microg x hr/ml. These findings are similar to those reported previously. Antacids did not alter these parameters significantly (Cmax of 5.62 +/- 2.53 microg/ml, Tmax of 0.71 +/- 0.56 hours, and AUC0-infinity of 20.27 +/- 11.39 microg x hr/ml). In contrast, the high-fat meal recommended by the Food and Drug Administration reduced INH Cmax by 51% (2.73 +/- 1.70 microg/ml), nearly doubled Tmax (1.93 +/- 1.61 hours), and reduced AUC0-infinity by 12% (17.72 +/- 10.32 microg x hr/ml). CONCLUSIONS: These changes in Cmax, Tmax, and AUC0-infinity can be avoided by giving INH on an empty stomach whenever possible.

Adult↗
PubMed1998

Rifampin stability.

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Administration, Oral↗
PubMed1998

Effect of grapefruit juice on clarithromycin pharmacokinetics.

To investigate whether grapefruit juice inhibits the metabolism of clarithromycin, 12 healthy subjects were given water or grapefruit juice before and after a clarithromycin dose of 500 mg in a randomized crossover study. Administration of grapefruit juice increased the time to peak concentration of both clarithromycin (82 +/- 35 versus 148 +/- 83 min; P = 0.02) and 14-hydroxyclarithromycin (84 +/- 38 min versus 173 +/- 85; P = 0.01) but did not affect other pharmacokinetic parameters.

Adult↗
PubMed1998

Oral cimetidine prolongs clarithromycin absorption.

The present study was conducted to identify any potential interaction between oral cimetidine and clarithromycin. Twelve healthy subjects were administered single doses of clarithromycin alone and with oral cimetidine dosed to steady state. Cimetidine prolonged the absorption of clarithromycin, as evidenced by decreased peak concentrations of both clarithromycin and 14-OH-clarithromycin (14OHC) in serum (46 and 43%, respectively), a delay in the formation of 14OHC (increase of 68%), and increases in both of their half-lives (75 and 82%, respectively), despite no changes in total oral clearance or area under the concentration-time curve for either compound. No mechanism for this interaction has been identified.

Absorption↗