Pharmacokinetics and pharmacodynamics in the treatment of cutaneous leishmaniasis - challenges and opportunities

TY - JOUR

T1 - Pharmacokinetics and pharmacodynamics in the treatment of cutaneous leishmaniasis - challenges and opportunities

AU - Van Bocxlaer, Katrien

AU - Croft, Simon L

N1 - This journal is © The Royal Society of Chemistry.

PY - 2021/1/7

Y1 - 2021/1/7

N2 - Pharmacological efficacy is obtained when adequate concentrations of a potent drug reach the target site. In cutaneous leishmaniasis, a heterogeneous disease characterised by a variety of skin manifestations from simple nodules, skin discoloration, plaques to extensive disseminated forms, the parasites are found in the dermal layers of the skin. Treatment thus involves the release of the active compound from the formulation (administered either topically or systemically), it's permeation into the skin, accumulation by the local macrophages and further transport into the phagolysosome of the macrophage. The pharmacodynamic activity of a drug against the parasite is relatively straight forward to evaluate both in vivo and in vitro. The pharmacokinetic processes taking place inside the skin are more complex to elucidate due to the multi-lamellar structure of the skin, heterogeneous distribution of drugs within the tissue, the difficulty of accessing the site of infection complicating sampling and the lack of surrogate markers reflecting the activity of a drug in the skin. This review will discuss the difficulties encountered when investigating drug distribution, PK PD relationships and efficacy in the skin with a focus on cutaneous leishmaniasis treatment.

AB - Pharmacological efficacy is obtained when adequate concentrations of a potent drug reach the target site. In cutaneous leishmaniasis, a heterogeneous disease characterised by a variety of skin manifestations from simple nodules, skin discoloration, plaques to extensive disseminated forms, the parasites are found in the dermal layers of the skin. Treatment thus involves the release of the active compound from the formulation (administered either topically or systemically), it's permeation into the skin, accumulation by the local macrophages and further transport into the phagolysosome of the macrophage. The pharmacodynamic activity of a drug against the parasite is relatively straight forward to evaluate both in vivo and in vitro. The pharmacokinetic processes taking place inside the skin are more complex to elucidate due to the multi-lamellar structure of the skin, heterogeneous distribution of drugs within the tissue, the difficulty of accessing the site of infection complicating sampling and the lack of surrogate markers reflecting the activity of a drug in the skin. This review will discuss the difficulties encountered when investigating drug distribution, PK PD relationships and efficacy in the skin with a focus on cutaneous leishmaniasis treatment.

U2 - 10.1039/d0md00343c

DO - 10.1039/d0md00343c

M3 - Review article

C2 - 34041488

SN - 2632-8682

VL - 12

SP - 472

EP - 482

JO - RSC Medicinal Chemistry

JF - RSC Medicinal Chemistry

IS - 4

ER -