Pharmacokinetic Evaluation of para‐Aminosalicylic Acid Granules

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Abstract
Study Objective. To determine the bioavailability and renal elimination of para‐aminosalicylic acid (PAS) and its inactive metabolite acetyl‐para‐aminosalicylic acid (AcPAS) from a new PAS formulation.Design. (a) Single‐dose pharmacokinetic study in healthy volunteers; (b) Day‐1 and day‐8 pharmacokinetic comparison in patients with multidrug‐resistant tuberculosis (MDR‐TB).Setting. Referral hospital that specializes in the treatment of mycobacterial infections.Patients. (a) Twelve healthy male and female volunteers recruited by the investigators. Eleven subjects (92%) completed the study; one subject could not maintain venous access and was removed from the study, (b) Six sequential male and female patients receiving multidrug treatment for advanced MDR‐TB. All patients completed the study.Interventions. (a) Volunteers received a single 4‐g dose of enteric‐coated PAS granules administered with food. Blood and urine samples were collected over 24 hours after the dose, (b) Patients received 4‐g doses of enteric‐coated PAS granules every 8 hours for 7 days as part of their treatment regimen. Blood samples were obtained at approximately 2,4, and 8 hours after the first dose on day 1 and the twenty‐second dose on day 8.Measurements and Main Results. Concentrations of PAS and AcPAS were determined using high‐performance liquid chromatography. The serum concentration‐time curves from volunteers and patients showed sustained PAS concentrations, in contrast to immediate‐release sodium PAS tablets. In the six patients with tuberculosis, day 8 concentrations were considerably higher than those on day 1, and all were sustained well above the PAS minimal inhibitory concentration for Mycobacterium tuberculosis.Conclusions. Para‐aminosalicylic acid granules produce adequate serum concentrations and appear to be safe.

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