Comment on: Skin pharmacokinetics of miltefosine in the treatment of post-kala-azar dermal leishmaniasis in South Asia

We would like to draw attention to two recent publications that provide insight into the pharmacokinetics (PK) of miltefosine in the treatment of post-kala-azar dermal leishmaniasis (PKDL). PKDL is a dermal complication that arises after suffering from visceral leishmaniasis, an infectious disease transmitted by sand flies. Both studies investigated target site PK of miltefosine in patients with PKDL; however, different sampling methods were used. We would like to discuss the differences of these methods and compare the study results. For clarity and ease of reading, all values in this article are presented in standardized units.

Wijnant et al.¹ (Experimental Parasitology, 2024) discussed the use of dermal microdialysis in the form of a proof-of-concept study to evaluate drug levels in the skin of one PKDL patient on Day 43 of miltefosine treatment. The patient received 50 mg of miltefosine twice daily for a total of 12 weeks. On the day the dermal microdialysis was performed, dialysates were sampled every 30 min over a period of 2.5 h—starting right after the intake of miltefosine 50 mg. Comparable unbound drug concentrations of around 400 ng/mL were found in lesional and non-lesional skin during the 2.5 h after dosing. No plasma sampling was performed in this study.

Palić et al.² (Journal of Antimicrobial Chemotherapy, 2024) conducted a clinical study with 52 PKDL patients using skin biopsies and plasma sampling to measure miltefosine concentrations. Patients weighing ≥45 kg received 150 mg of miltefosine, divided into two administrations, for a total of 21 days. A single skin biopsy was taken on Day 22—around 24 h after the last dose of miltefosine. Additionally, miltefosine plasma samples were taken on study Days 8, 15, 22, and 30 and at 3 months. As the invasive nature of the skin biopsy might have led to a flare-up of the infection, the biopsy was taken out of non-lesional skin. The median skin miltefosine concentration on Day 22 was 43 730 ng/g (IQR: 21 940–60 650 ng/g), whereas the median plasma concentration was 33 290 ng/mL (IQR: 25 900–42 580 ng/mL).

Given that miltefosine has a protein binding rate of approximately 95%–98% in human plasma^3,4 and assuming that the unbound fraction is similar in tissue, the unbound concentration in Palić et al.’s study is expected to range between 439 and 1213 ng/g in skin using a protein binding of 98%. This estimate aligns closely with the free miltefosine tissue concentration of around 400 ng/mL reported by Wijnant et al.,¹ bearing in mind that the daily miltefosine dose in Wijnant et al.’s study was 100 mg, whereas Palić et al.’s² study used allometric dosing, resulting in a daily dose closer to 150 mg. However, while both skin biopsy and dermal microdialysis were performed when miltefosine reached steady state, the time intervals after the last dose of miltefosine differed between the studies.

Overall, both dermal microdialysis and skin biopsy are established techniques for measuring drug levels in the skin.⁵ While lesional tissue may provide a more accurate representation of the drug’s activity at the target site, it carries a higher risk of complications. Both sampling in lesional and non-lesional tissues therefore have their own advantages and limitations, and the choice between them depends on the balance between accuracy and patient safety. Dermal microdialysis is a less invasive alternative that may be particularly suitable for use in lesional skin, with a lower risk of inducing disease flares.

In the microdialysis study by Wijnant et al., the catheter was placed in the dermis beneath the lesion. It is therefore reasonable to assume that lesional tissue was included, ensuring that drug concentrations in the affected area were accurately captured, but it cannot be ruled out that non-infected parts of the tissue were also included. In addition, the lesion itself may be heterogeneous and therefore drug penetration may vary between the centre of the lesion and the border where infected and non-infected tissues meet.

Due to the invasive nature of biopsies, only a single timepoint was chosen in Palić et al.’s study, which limits the ability to capture a dynamic PK profile and assess the relationship between drug levels and therapeutic response over time. Unlike skin biopsy, dermal microdialysis is able to continuously measure drug concentrations over time, which enables a more detailed characterization of the PK profile compared to a single biopsy.

Furthermore, dermal microdialysis provides a more accurate assessment of drug concentration in the extracellular space by specifically measuring the unbound fraction of the drug, which is the pharmacologically active component responsible for the drug’s efficacy. In contrast, skin biopsy tends to be less accurate as it combines drug concentrations from both intracellular and extracellular compartments. This can potentially obscure important details of drug distribution and action, and additional assumptions such as those presented above must be made to estimate the unbound fraction.⁵

Apart from the two methods discussed in the cited publications, other valuable techniques, such as the skin blister technique or positron emission tomography (PET) imaging, are available for measuring drug concentrations in tissues. The skin blister technique is a minimally invasive method that provides a good representation of drug levels in the interstitial fluid of the skin, while PET offers a non-invasive approach to visualize and quantify drug distribution throughout the entire body, including the skin.^5,6 However, the ability to measure the unbound drug fraction specifically in the extracellular space is a unique advantage of dermal microdialysis.⁷

The technique of dermal microdialysis could find use in the quantification of drug concentrations in various challenging infectious diseases such as bacterial infections (e.g. non-tuberculous mycobacteria and endemic treponematoses, like pinta, bejel, and yaws), fungal infections with skin involvement (e.g. histoplasmosis and cryptococcosis), or parasitic infections (e.g. onchocerciasis and cysticercosis). In general, there is a significant lack in PK studies and especially in target site investigations in neglected tropical diseases. Such studies would offer valuable information about the actual drug concentration at its site of action and would therefore be crucial to further optimize treatment regimens.^8,9

Funding

This study was carried out as part of our routine work.

Transparency declarations

The authors do not have any conflict of interest directly relevant to the content of this correspondence.

References