Pharmacokinetic Evaluation of <i>para</i>‐Aminosalicylic Acid Granules

Peloquin, Charles A.; Henshaw, Thomas L.; Huitt, Gwen A.; Berning, Shaun E.; Nitta, Annette T.; James, Gordon T.

doi:10.1002/j.1875-9114.1994.tb02787.x

Cited by 36 publications

(40 citation statements)

References 6 publications

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“…Previous studies of GSR-PAS have found that 4-g doses twice daily were sufficient to maintain PAS concentrations above the MIC during a dosing interval but that a once-daily 4-g dose is insufficient for this purpose (3,4). Our study found that although a minority of patients maintain concentrations above 1 mg/liter following oncedaily dosing with 8 g GSR-PAS, half of the patients studied had C 0 values of Ͻ1 mg/liter with a median %TϾMIC of 94.6%.…”

Section: Discussionmentioning

confidence: 99%

N -Acetyltransferase Genotypes and the Pharmacokinetics and Tolerability of para -Aminosalicylic Acid in Patients with Drug-Resistant Pulmonary Tuberculosis

Kock

Diacon

et al. 2015

Antimicrob Agents Chemother

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h The aim of this study was to examine the relationships between N-acetyltransferase genotypes, pharmacokinetics, and tolerability of granular slow-release para-aminosalicylic acid (GSR-PAS) in tuberculosis patients. The study was a randomized, two-period, open-label, crossover design wherein each patient received 4 g GSR-PAS twice daily or 8 g once daily alternately. The PAS concentration-time profiles were modeled by a one-compartment disposition model with three transit compartments in series to describe its absorption. Patients' NAT1 and NAT2 genotypes were determined by sequencing and restriction enzyme analysis, respectively. The number of daily vomits was modeled by a Poisson probability mass function. Comparisons of other tolerability measures by regimens, gender, and genotypes were evaluated by a linear mixed-effects model. The covariate effects associated with efavirenz, gender, and NAT1*3, NAT1*14, and NAT2*5 alleles corresponded to 25, 37, ؊17, ؊48, and ؊27% changes, respectively, in oral clearance of PAS. The NAT1*10 allele did not influence drug clearance. The time above the MIC of 1 mg/liter was significantly different between the two regimens but not influenced by the NAT1 or NAT2 genotypes. The occurrence and intensity of intolerance differed little between regimens. Four grams of GSR-PAS twice daily but not 8 g once daily ensured concentrations exceeding the MIC (1 mg/liter) throughout the dosing interval; PAS intolerance was not related to maximum PAS concentrations over the doses studied and was not more frequent after once-daily dosing. We confirm that the slow phenotype conferred by the NAT1*14 and NAT1*3 alleles resulted in higher PAS exposure but found no evidence of increased activity of the NAT1*10 allele. p ara-Aminosalicylic acid (PAS) was the first effective antituberculosis agent used to treat pulmonary tuberculosis (1); for a duration of 20 to 25 years, it was part of the standard "first-line" tuberculosis treatment (2). Valued for preventing resistance in companion drugs, it was nonetheless notorious for gastrointestinal intolerance, causing frequent nausea, vomiting, and abdominal discomfort. The replacement of PAS with rifampin and ethambutol was greeted with relief by patients, but with widespread multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis in a number of countries, particularly in the developing world, PAS is again being used to treat drug-resistant tuberculosis.The PAS preparation most commonly used in many countries is the granular slow-release (delayed-release) formulation (GSR-PAS), which prevents premature drug release in the stomach, avoiding the high PAS concentrations considered prone to cause intolerance. Several studies (3-7) have reported PAS concentrations associated with use of GSR-PAS in dosages from 4 g daily to 8 to 12 g daily in divided doses, as recommended by the World Health Organization (8). As PAS is usually considered bacteriostatic, divided dosing aims to provide concentrations consistently exceeding the PAS MIC of approx...

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Section: Discussionmentioning

confidence: 99%

N -Acetyltransferase Genotypes and the Pharmacokinetics and Tolerability of para -Aminosalicylic Acid in Patients with Drug-Resistant Pulmonary Tuberculosis

Kock

Diacon

et al. 2015

Antimicrob Agents Chemother

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“…For nearly 2 decades, a granular slow-release form of PAS (para-aminosalicylic acid delayed-release granules [PASER granules]) has been available and has been found to cause less intolerance in several studies in TB patients and healthy volunteers (12,13). This formulation still provides PAS concentrations exceeding the MIC of PAS when given at 4 g twice daily.…”

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confidence: 99%

“…This formulation still provides PAS concentrations exceeding the MIC of PAS when given at 4 g twice daily. It was also shown that 4 g once daily failed to maintain concentrations above the MIC over a 24-h dosing interval (12,13). Although PAS has been in use for more than 60 years and was extensively studied, little is known about the pharmacokinetics of PAS in HIV-infected patients and potential interactions of PAS with other coadministered second-line TB drugs and antiretroviral (ARV) medications, and the currently available PAS formulation (PASER) has been the subject of relatively few pharmacokinetic studies (12)(13)(14).…”

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confidence: 99%

Pharmacokinetics ofpara-Aminosalicylic Acid in HIV-Uninfected and HIV-Coinfected Tuberculosis Patients Receiving Antiretroviral Therapy, Managed for Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis

Kock

Rosenkranz

et al. 2014

Antimicrob Agents Chemother

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dThe emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis prompted the reintroduction of para-aminosalicylic acid (PAS) to protect companion anti-tuberculosis drugs from additional acquired resistance. In sub-Saharan Africa, MDR/XDR tuberculosis with HIV coinfection is common, and concurrent treatment of HIV infection and MDR/XDR tuberculosis is required. Out of necessity, patients receive multiple drugs, and PAS therapy is frequent; however, neither potential drug interactions nor the effects of HIV infection are known. Potential drug-drug interaction with PAS and the effect of HIV infection was examined in 73 pulmonary tuberculosis patients; 22 (30.1%) were HIV coinfected. Fortyone pulmonary MDR or XDR tuberculosis patients received 4 g PAS twice daily, and in a second crossover study, another 32 patients were randomized, receiving 4 g PAS twice daily or 8 g PAS once daily. A PAS population pharmacokinetic model in two dosing regimens was developed; potential covariates affecting its pharmacokinetics were examined, and Monte Carlo simulations were conducted evaluating the pharmacokinetic-pharmacodynamic index. The probability of target attainment (PTA) to maintain PAS levels above MIC during the dosing interval was estimated by simulation of once-, twice-, and thrice-daily dosing regimens not exceeding 12 g daily. Concurrent efavirenz (EFV) medication resulted in a 52% increase in PAS clearance and a corresponding >30% reduction in mean PAS area under the concentration curve in 19 of 22 HIV-M. tuberculosis-coinfected patients. Current practice recommends maintenance of PAS concentrations at >1 g/ml (the MIC of M. tuberculosis), but the model predicts that at only a minimum dose of 4 g twice daily can this PTA be achieved in at least 90% of the population, whether or not EFV is concomitantly administered. Once-daily dosing of 12 g PAS will not provide PAS concentrations exceeding the MIC over the entire dosing interval if coadministered with EFV, while 4 g twice daily ensures concentrations exceeding MIC over the entire dosing interval, even in HIV-infected patients who received EFV.

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“…There was no monitoring and their quality, and exhaustivity, remain limited and cannot be assimilated to data from a prospective clinical trial. Evidence of efficacy/safety of PAS was in the treatment of TB where the combination with streptomycin or isoniazid was associated with a dramatic decline in resistant organisms compared with monotherapy regimens [2,3], and only relatively small numbers of patients receiving the present new formulation have been reported in the literature [4,5,6,7,8] Moreover PAS was associated with GI side effects in 58% of patients [2]. …”

Section: Discussionmentioning

confidence: 99%

“…cured, lost to follow-up, adverse event, AE) and the description of AE. Furthermore, the safety of PAS-GR was summarized from the incidence of AE in all 362 subjects who received the drug and were either included under the present ATU cohort or published from clinical studies [4,5,6,7,8], as well as in 33 pediatric TB patients (ex-ATU patients in France and in one publication [8]). All ATU patients were included in the analysis.…”

Section: Methodsmentioning

confidence: 99%

French Nationwide Cohort Temporary Utilization Authorization Survey of GranuPAS® in MDR-TB Patients

Kibleur

Véziris²

2014

Chemotherapy

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Background: Para-aminosalicylic acid (PAS) is again needed for the treatment of multidrug and extensively drug-resistant tuberculosis (M/XDR-TB). The study of a new granulated formulation (PAS-GR, ‘GranuPAS®'), which might have fewer adverse events, was made possible by the statutory requirement that data be collected regarding its use in France in multidrug-resistant TB (MDR-TB) patients under a ‘therapeutic utilization' follow-up for safety and efficacy system called ‘Autorisation Temporaire d'Utilisation' (ATU). Methods: In May 2011 an ATU cohort was established to monitor the named patient use of PAS-GR. All patients were included in a follow-up protocol developed by Lucane Pharma and the French Medicines Agency (ANSM) which recorded demographics, dosing characteristics, concomitant medications, adverse events, and outcome. Following EU marketing authorization, the ATU terminated about 3 years after initiation. Results: PAS-GR was used for the treatment of 231 MDR-TB patients. PAS-GR was used at 12 g/day in 114 cases and 8 g/day in 80 cases. PAS-GR-containing combinations resulted in sputum conversion in a median of 94 days (IQR 48-143) in the 55 patients with information after treatment initiation. Adverse effects of PAS-GR-containing combinations were mostly gastrointestinal (GI; 9% of patients experiencing a GI event at any time) and led to interrupt PAS-GR in 6% of cases (2.1% GI). Conclusions: The efficacy of PAS-GR appears equivalent to that of PAS, and its tolerance improved over earlier PAS formulations, thus supporting the use of PAS-GR as part of drug combinations for the treatment of MDR and XDR-TB.

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Pharmacokinetic Evaluation of para‐Aminosalicylic Acid Granules

Abstract: Para-aminosalicylic acid granules produce adequate serum concentrations and appear to be safe.

Cited by 36 publications

References 6 publications

N -Acetyltransferase Genotypes and the Pharmacokinetics and Tolerability of para -Aminosalicylic Acid in Patients with Drug-Resistant Pulmonary Tuberculosis

N -Acetyltransferase Genotypes and the Pharmacokinetics and Tolerability of para -Aminosalicylic Acid in Patients with Drug-Resistant Pulmonary Tuberculosis

Pharmacokinetics ofpara-Aminosalicylic Acid in HIV-Uninfected and HIV-Coinfected Tuberculosis Patients Receiving Antiretroviral Therapy, Managed for Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis

French Nationwide Cohort Temporary Utilization Authorization Survey of GranuPAS® in MDR-TB Patients

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