Pharmacokinetic optimisation in the treatment of Pneumocystis carinii pneumonia

Abstract

Several drugs and drug combinations are currently used in the treatment of patients with Pneumocystis carinii pneumonia (PCP)--pentamidine and cotrimoxazole (trimethoprim plus sulphamethoxazole), which are indicated for this usage, dapsone/trimethoprim and clindamycin/primaquine, which are not licensed for PCP, and trimetrexate/calcium folinate (leucovorin), eflornithine and BW-566C (566 C80) as investigational drugs. For most of these agents, recommendations regarding the use of pharmacokinetic parameters to establish individualised therapy cannot be made. The pharmacokinetics of antipneumocystis drugs are not well documented and clinical trials evaluating the relationship between the individual plasma pharmacokinetic profiles and responses to treatment are sparse. In clinical trials, the reduction of the daily dose of pentamidine to 3 or 2 mg/kg/day and of cotrimoxazole to 15 mg/kg of the trimethoprim component resulted in a substantial reduction of frequency and severity of adverse drug effects without diminishing efficacy. For pentamidine, a long half-life of > or = 4 days implies the need for a loading dose. Plasma concentrations of the parent drug at steady-state varied between 30 and 100 micrograms/L. The elimination pharmacokinetics are characterised by several elimination slopes indicating the existence of a deep peripheral compartment. Due to its very low renal clearance, dosage adjustments are not necessary in patients with renal impairment. The pharmacokinetics of cotrimoxazole follow first-order kinetics in PCP and the particular parameters are similar to those reported in the treatment of bacterial infection. Steady-state plasma concentrations of both trimethoprim and sulphamethoxazole are attained within 2 to 3 days, but the range of 'therapeutic' plasma concentrations must be newly defined, since elevated trimethoprim concentrations could not be correlated with the frequency and severity of adverse drug reactions. The concentrations of sulphamethoxazole may be at least as important as those of trimethoprim in defining a toxic range. With dapsone/trimethoprim, clindamycin/primaquine and BW-566C (566 C 80) good clinical response rates were found in groups of patients with mild to moderate PCP. Comparative trials with standard drugs are still ongoing. Therapeutic to toxic concentration ratios have not been established in patients with PCP. Pharmacokinetic data pertaining to patients with PCP are either nonexistent or incomplete, or are complicated by a drug interaction between dapsone and trimethoprim suggesting an inhibition of metabolism of dapsone. Eflornithine and trimetrexate/calcium folinate have been used under specific research protocols, showing partial success as salvage agents for desperately ill patients with AIDS. Regarding all antipneumocystis drugs, additional clinical and pharmacokinetic data are needed to optimise and more fully individualise the treatment regimens for this severe infection.