PHARMACOKINETIC OPTIMIZATION IN THE TREATMENT OF PNEUMOCYSTIS-CARINIIPNEUMONIA

Several drugs and drug combinations are currently used in the treatmen t of patients with Pneumocystis carinii pneumonia (PCP) - pentamidine and cotrimoxazole (trimethoprim plus sulphamethoxazole), which are ind icated for this usage, dapsone/trimethoprim and clindamycin/primaquine , which are not licensed for PCP, and trimetrexate/calcium folinate (l eucovorin), eflornithine and BW-566C (566 C80) as investigational drug s. For most of these agents, recommendations regarding the use of phar macokinetic parameters to establish individualised therapy cannot be m ade. The pharmacokinetics of antipneumocystis drugs are not well docum ented and clinical trials evaluating the relationship between the indi vidual plasma pharmacokinetic profiles and responses to treatment are sparse. In clinical trials, the reduction of the daily dose of pentami dine to 3 or 2 mg/kg/day and of cotrimoxazole to 15 mg/kg of the trime thoprim component resulted in a substantial reduction of frequency and severity of adverse drug effects without diminishing efficacy. For pe ntamidine, a long half-life of greater-than-or-equal-to 4 days implies the need for a loading dose. Plasma concentrations of the parent drug al steady-state varied between 30 and 100 mug/L. The elimination phar macokinetics are characterised by several elimination slopes indicatin g 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 tho se reported in the treatment of bacterial infection. Steady-state plas ma concentrations of both trimethoprim and sulphamethoxazole are attai ned within 2 to 3 days, but the range of 'therapeutic' plasma concentr ations must be newly defined, since elevated trimethoprim concentratio ns could not be correlated with the frequency and severity of adverse drug reactions. The concentrations of sulphamethoxazole may be at leas t as important as those of trimethoprim in defining a toxic range. Wit h dapsone/trimethoprim, clindamycin/primaquine and BW-566C (566 C 80) good clinical response rates were found in groups of patients with mil d to moderate PCP. Comparative trials with standard drugs are still on going. Therapeutic to toxic concentration ratios have not been establi shed 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 inhi bition of metabolism of dapsone. Eflornithine and trimetrexate/calcium folinate have been used under specific research protocols, showing pa rtial success as salvage agents for desperately ill patients with AIDS . Regarding all antipneumocystis drugs, additional clinical and pharma cokinetic data are needed to optimise and more fully individualise the treatment regimens for this severe infection.