Date Published: May 28, 2008
Publisher: Public Library of Science
Author(s): Thomas P. C. Dorlo, Piet A. Kager, Juerg Utzinger
Abstract: Pentamidine has a long history in the treatment of human African trypanosomiasis (HAT) and leishmaniasis. Early guidelines on the dosage of pentamidine were based on the base-moiety of the two different formulations available. Confusion on the dosage of pentamidine arose from a different labelling of the two available products, either based on the salt or base moiety available in the preparation. We provide an overview of the various guidelines concerning HAT and leishmaniasis over the past decades and show the confusion in the calculation of the dosage of pentamidine in these guidelines and the subsequent published reports on clinical trials and reviews. At present, only pentamidine isethionate is available, but the advised dosage for HAT and leishmaniasis is (historically) based on the amount of pentamidine base. In the treatment of leishmaniasis this is probably resulting in a subtherapeutic treatment. There is thus a need for a new, more transparent and concise guideline concerning the dosage of pentamidine, at least in the treatment of HAT and leishmaniasis.
Partial Text: The finding of the antiprotozoal activity of the diamidine family of drugs was largely a matter of serendipity. They were discovered during a search for hypoglycaemic compounds that could affect trypanosomes. Of the compounds synthesized, pentamidine (Figure 1) proved to be the most useful, and since the early 1940s it has been used in the treatment and prophylaxis of human African trypanosomiasis (HAT, also known as sleeping sickness) and to some extent in the treatment of visceral leishmaniasis in India. Nowadays, pentamidine is mainly used for prophylaxis and treatment of Pneumocystis jirovecii pneumonia (PCP), and in the treatment of first-stage HAT and of several forms of American cutaneous leishmaniasis.
From the first published guidelines onwards, the dosage of pentamidine was expressed in and based on the active ingredient, the pentamidine base-moiety of the salt preparations. Pentamidine isethionate contains 1 g of base per 1.74 g of salt, while pentamidine methanesulfonate contains 1 g of base per 1.56 g of salt. The labelling of the ampoules of the different products is a source of confusion; pentamidine isethionate is labelled according to the amount of salt in the preparation (300 mg salt per ampoule), while pentamidine methanesulfonate was labelled according to the base-moiety (120 mg base per ampoule). The successive guidelines of the World Health Organization (WHO) for pentamidine in the treatment of Trypanosoma brucei gambiense infection as found in the WHO Technical Report Series demonstrate this confusion. In the first report of 1962, one reads that “3–4 mg of base/kg of body-weight” per injection should be administered .
In the WHO Technical Report Series pertaining to the leishmaniases, 4 mg/kg is mentioned without indication of base or salt ,. An extensive review of the treatment of the leishmaniases does not mention the differences in composition and dosing of the two preparations . Differences in efficacies are described for various types of leishmaniasis and for various regions, but without knowing the amount of actual product given, it remains difficult to assess the data . After interruption of the production of pentamidine methanesulfonate, the differences between the two salts of pentamidine and their labelling and the resulting difference in efficacy rates were already noticed in the treatment of South American leishmaniasis . In French Guyana, cutaneous leishmaniasis caused by Leishmania guyanensis was treated with 4 mg/kg pentamidine methanesulfonate (thus, 4 mg pentamidine base/kg). When, in 1992, pentamidine isethionate replaced pentamidine methanesulfonate and was used at the same dose of 4 mg/kg, clinicians noticed a decreased efficacy. A dose of 7 mg pentamidine isethionate/kg, equivalent to 4 mg pentamidine base/kg, restored effectiveness . Also, in the treatment of visceral leishmaniasis in India, a difference in response to the two pentamidine formulations was noticed . After the disappearance of pentamidine methanesulfonate from the Indian market, pentamidine isethionate was used at the “same” dosage of 4 mg/kg, and a reduction in efficacy as well as toxicity was observed . Most probably, the dosage was based on the labelling and thus only 2.3 mg/kg base (4 mg/kg pentamidine isethionate) was administered. Retrospectively, the observed higher relapse rate and less distinct toxicity profile in these visceral leishmaniasis patients was not caused by a different kind of pentamidine salt, but by an inherent, unnoticed change of dosage.
There is a need for a more transparent guideline concerning pentamidine, at least for the treatment of HAT and leishmaniasis. The former availability of different salts of pentamidine and their differences in the amount of active ingredient and labelling of the preparation led to great confusion in guidelines and reviews, and reports on clinical trials. In the future, it should clearly be stated which preparation is used and on which moiety of the preparation (either salt or base) the mentioned dosage is based. Since only pentamidine isethionate is available at the moment and this preparation is labelled according to the amount of salt, a scheme involving the volume of pentamidine isethionate solution to administer per kilogram of body weight seems most rational as a practical guideline for nurses and clinical officers. This should rule out any inconsistent dosing determining falsely the dose–efficacy relationship and will make future clinical trials better comparable.