Pharmacokinetics and adverse reactions after a single dose of pentamidine in patients with Trypanosoma gambiense sleeping sickness.

Abstract

1 Plasma concentrations of pentamidine were measured up to 1-8 months after a single 2 h i.v. infusion of 3.0 to 4.8 mg kg-1 pentamidine isethionate in 11 patients with late stage Trypanosoma gambiense sleeping sickness. 2 Maximum plasma drug concentrations varied between 713 and 2461 nmol 1-1.After termination of infusion, a rapid distribution phase over 10 min was followed by a slower distribution phase and an elimination phase prolonged over weeks to months. 3 The 'terminal'"elimination rate constant could be determined in six patients and subsequent kinetic calculations showed a three to fourfold variation in plasma clearance and 'terminal' half-life (median 1126 (range 553-2036) ml min-1 and 265 (107-446) h, respectively). The median apparent volume of distribution (Vss) was 11 850 1. Renal clearance accounted for a median of 11% of total plasma clearance, indicating that metabolism is a major route of pentamidine elimination in man. 4 Side effects were few and mild and a slight or moderate decrease in blood pressure was the most common registered adverse reaction observed in four subjects. 5 The prolonged elimination of pentamidine seems inconsistent with the present recommended dosage regimen of pentamidine for treatment of trypanosomiasis of 7 to 10 parenteral doses given once daily or every second day.

Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT)

“…S2). 39 Pentamidine is administered during early stage disease; whereas, melarsoprol or a combination of nifurtimox/eflornithine are used during the late stage. These drugs are not only difficult to administer but also toxic, in particular the arsenical melarsoprol provokes fatal outcomes in 10% of patients.…”

Chemotherapy against human African trypanosomiasis: Is there a road to success?

“…The stable very low relapse rate, despite the extensive former use in prophylaxis programmes (Waddy, 1970), may be due to the uptake of the molecule by three different transporters (Barrett et al 2007). Pharmacokinetic evidence indicates that three injections may be equally effective (Bronner et al 1991;Bronner, 1994) and a respective comparative clinical trial is currently ongoing to evaluate this (ISRCTN55042030). Due to the high potency of pentamidine and the low drug levels detected in the CSF (Bronner et al 1991) the use to treat 'intermediate stage' patients (up to 10 or 20 white blood cells (WBC) mm − 3 in CSF) was suggested (Doua et al 1996).…”

“…Pharmacokinetic evidence indicates that three injections may be equally effective (Bronner et al 1991;Bronner, 1994) and a respective comparative clinical trial is currently ongoing to evaluate this (ISRCTN55042030). Due to the high potency of pentamidine and the low drug levels detected in the CSF (Bronner et al 1991) the use to treat 'intermediate stage' patients (up to 10 or 20 white blood cells (WBC) mm − 3 in CSF) was suggested (Doua et al 1996). The resulting efficacy in respective studies is equivocal (Ruiz et al 2002;Lejon et al 2003;Balasegaram et al 2006b).…”

In vitro activity of pentamidine against Tropheryma whipplei

“…Interestingly, it has been demonstrated that pentamidine may accumulate in rat liver lysosomes [14], the niche of intracellular multiplication of T. whipplei, which may explain why the MICs observed in cell culture assay tend to be lower compared with the axenic medium assay, and why pentamidine was effective in vitro against C. burnetii in cells. MICs against T. whipplei in the current study were lower compared with plasma concentrations of pentamidine, which have been reported to range from 0.25 mg/L to 8.0 mg/L during treatment of Trypanosoma gambiense infections [15]. Pentamidine is known to have a large volume of distribution and a very long elimination half-time that reflect the pronounced tissue affinity of the drug.…”