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Dorlo, Thomas P. C., PhDORCID iD iconorcid.org/0000-0003-3076-8435
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Publications (10 of 68) Show all publications
Schouten, W. M., Van Bocxlaer, K., Rosing, H., Huitema, A. D., Beijnen, J. H., Kratz, J. M., . . . Dorlo, T. (2025). Development and validation of ultra-performance liquid chromatography tandem mass spectrometry methods for the quantitative analysis of the antiparasitic drug DNDI-6148 in human plasma and various mouse biomatrices. Journal of chromatography. B, 1250, Article ID 124377.
Open this publication in new window or tab >>Development and validation of ultra-performance liquid chromatography tandem mass spectrometry methods for the quantitative analysis of the antiparasitic drug DNDI-6148 in human plasma and various mouse biomatrices
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2025 (English)In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 1250, article id 124377Article in journal (Refereed) Published
Abstract [en]

DNDI-6148 is a promising new oral drug for the treatment of cutaneous leishmaniasis (CL), a parasitic neglected tropical disease that affects impoverished populations worldwide. Preclinical target site pharmacokinetics (PK) studies are necessary to evaluate the actual exposure to DNDI-6148 of Leishmania parasites in the skin. To facilitate these investigations, we have developed and validated a reversed phase ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method to quantify DNDI-6148 in relevant target site PK samples, adhering to the relevant International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M10 guideline on bioanalytical method validation. Full validation was performed for the surrogate biomatrices human K2EDTA plasma, enzymatic digestion buffer and skin microdialysate. Partial validation was conducted for mouse K2EDTA plasma and tissues. The tissue samples, including mouse skin, liver and spleen, were homogenized using a collagenase A-based enzymatic homogenization workflow. This method was found to be 2.9-fold more effective in extracting DNDI-6148 from skin than the commonly used mechanical homogenization. Protein precipitation was subsequently carried out for all biomatrices. A surrogate biomatrix was used for each method and the range was specifically developed for its intended application, resulting in a linear concentration range of 5.00-2000 ng/mL, 2.00-1000 ng/mL, and 3.00-600 ng/mL for human K2EDTA plasma, enzymatic digestion buffer and microdialysate, respectively. Each biomatrix had intra- and inter-run accuracy and precision within 15 % for all concentration levels. Matrix effects did not affect the determination of DNDI-6148, since the stable isotopically-labelled internal standard for DNDI-6148 effectively compensated for these matrix effects. Total recovery across all methods was between 73.5 % and 81.3 % (CV ≤4.5 %). DNDI-6148 was stable under various conditions in all the tested biomatrices. However, a decrease in its concentration was observed during homogenization, for which the internal standard corrected adequately. The suitability of the method for use in future preclinical research involving DNDI-6148 was demonstrated in a preclinical target site PK study using a CL-infected murine model.

Place, publisher, year, edition, pages
Elsevier, 2025
Keywords
DNDI-6148, Leishmaniasis, Target site pharmacokinetics, UPLC-MS/MS
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-548685 (URN)10.1016/j.jchromb.2024.124377 (DOI)001441987700001 ()39577310 (PubMedID)2-s2.0-85209659303 (Scopus ID)
Available from: 2025-01-28 Created: 2025-01-28 Last updated: 2025-03-20Bibliographically approved
van den Berg, S. P. H., Adolfsen, P. E. A., Dorlo, T. P. C. & Rispens, T. (2025). Does one model fit all mAbs?: An evaluation of population pharmacokinetic models. mAbs, 17(1), Article ID 2512217.
Open this publication in new window or tab >>Does one model fit all mAbs?: An evaluation of population pharmacokinetic models
2025 (English)In: mAbs, ISSN 1942-0862, E-ISSN 1942-0870, Vol. 17, no 1, article id 2512217Article in journal (Refereed) Published
Abstract [en]

Antibodies are extensively used in treating various diseases, with over 100 canonical monoclonal antibodies (mAbs) approved. Population pharmacokinetic (PK) models are typically developed for each individual mAb, despite their similarities in size, shape, and susceptibility to lysosomal degradation. However, sparse datasets with limited PK information pose challenges in deriving accurate parameter estimates. Here, we provide a comprehensive overview of 160 published models of 69 mAbs, administered either intravenously or subcutaneously, examining their structural, statistical, and covariate components. Median estimates for the base parameters are linear clearance (0.22 L/d), central volume (3.42 L), peripheral volume (2.68 L), intercompartmental clearance (0.54 L/d), absorption rate (0.25 L/d), and bioavailability (69%). Using these to simulate a 'generic' mAb results in plausible kinetics with a terminal half-life of 21 ds. We demonstrated that the median linear clearance was 26% lower in models that included nonlinear target-mediated kinetics, when compared to linear models (0.18 vs. 0.25 L/d). For chimeric mAbs median linear clearance was 50% higher compared to fully human and humanized mAbs. Variability in PK parameter estimates across models was comparable to the inter-individual variability, which have consistently shown to be large for mAbs PK (e.g. 55% vs. 43% for clearance and 25% vs. 30% for central volume, respectively). Our meta-analysis suggests that a priori parameter estimates derived from the large body of existing pharmacokinetic models for mAbs are representative for many mAbs and can facilitate the design of new and/or more complex pharmacokinetic models or assist in dose optimization models.

Place, publisher, year, edition, pages
Taylor & Francis, 2025
Keywords
Biologics, generic model, linear clearance, meta-analysis, models, monoclonal antibodies, population pharmacokinetics, target-mediated drug disposition
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-559519 (URN)10.1080/19420862.2025.2512217 (DOI)001499444400001 ()40447562 (PubMedID)
Available from: 2025-06-13 Created: 2025-06-13 Last updated: 2025-06-13Bibliographically approved
Hooijberg, F., van den Berg, S. P. H., Layegh, Z., Leeuw, M., Elkayam, O., de Vries, A., . . . Wolbink, G. (2025). Precision Dosing of Intravenous Tocilizumab: Development of Pharmacokinetic Model–Derived Tapering Strategies for Patients With Rheumatoid Arthritis. Therapeutic Drug Monitoring, 47(3), 337-345
Open this publication in new window or tab >>Precision Dosing of Intravenous Tocilizumab: Development of Pharmacokinetic Model–Derived Tapering Strategies for Patients With Rheumatoid Arthritis
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2025 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 47, no 3, p. 337-345Article in journal (Refereed) Published
Abstract [en]

Background: 

Tocilizumab targets the interleukin-6 receptor, and dosing is complex owing to its nonlinear clearance related to target binding. Therefore, tapering tocilizumab requires a different approach than that of tumor necrosis factor inhibitors (TNFi). This study aimed to identify these differences and enable personalized treatment of rheumatoid arthritis (RA) beyond TNFi therapy.

Methods: 

A population pharmacokinetic model of intravenous tocilizumab was developed using data from a randomized controlled trial of dose tapering in patients with RA. Subsequent population-level Monte Carlo and individual Bayesian simulations were performed to create tapering strategies involving dose reduction and interval extension. The target trough concentration of tocilizumab was 5 mg/L. Finally, the drug savings were compared between the 2 methods.

Results: 

The pharmacokinetic of tocilizumab was described with a 2-compartment model with parallel linear (CL 0.20 L/d) and nonlinear (VM 5.2 mg/d, KM 0.19 mg/L) elimination. The linear clearance rate and central volume of distribution increased with lean body mass, and men exhibited higher clearance rates than women. The simulated concentration–time profiles demonstrated that, owing to nonlinear clearance, drug concentrations decreased more than dose-proportionally with lower doses. Tapering based on an individual Bayesian approach emerged as the most promising strategy, yielding a 39% reduction in drug use across virtual populations.

Conclusions: 

Tapering strategies were developed for intravenous tocilizumab, offering potential application in patients with RA who have reached low disease activity or remission, pending clinical validation. The developed strategies demonstrate that the tapering of tocilizumab should be approached more carefully and in smaller steps than that of TNFi.

Place, publisher, year, edition, pages
Wolters Kluwer, 2025
Keywords
tocilizumab, therapeutic drug monitoring, pharmacokinetics, simulation
National Category
Pharmacology and Toxicology Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-545196 (URN)10.1097/ftd.0000000000001258 (DOI)001484632700007 ()2-s2.0-85209750825 (Scopus ID)
Available from: 2024-12-12 Created: 2024-12-12 Last updated: 2025-05-23Bibliographically approved
Schouten, W. M., Van Bocxlaer, K., Rosing, H., Huitema, A. D. R., Beijnen, J. H., Kratz, J. M., . . . Dorlo, T. P. C. (2025). Quantitative analysis of DNDI-6174 using UPLC-MS/MS: A preclinical target site pharmacokinetic study. Journal of chromatography. B, 1262, Article ID 124652.
Open this publication in new window or tab >>Quantitative analysis of DNDI-6174 using UPLC-MS/MS: A preclinical target site pharmacokinetic study
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2025 (English)In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 1262, article id 124652Article in journal (Refereed) Published
Abstract [en]

Leishmaniasis is a neglected parasitic infection that continues to pose a significant global health challenge, with currently limited effective treatment options. DNDI-6174 is a novel orally-active, investigational drug with antileishmanial properties. Herein, a novel ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify DNDI-6174 in relevant murine biomatrices, i.e., K2EDTA plasma and enzymatically-homogenized skin, spleen and liver to support the translational pharmacokinetic-pharmacodynamic model-informed drug development. The chromatographic system consisted of a gradient elution on a standard C18 column connected to a triple quadrupole MS, operating in positive ionization mode. Pre-processing of murine tissues with collagenase A led to a superior homogenization and analyte extraction compared to mechanical disruption. Human K2EDTA plasma served as a surrogate matrix, enabling accurate (bias between −12.0 % and 9.8 %) and precise (relative standard deviation (RSD) ≤ 12.5 %) quantification of DNDI-6174 in the various murine biomatrices. Sample processing with tert-methylbutyl ether resulted in a reproducible recovery between 70.0 % and 93.8 % (RSD ≤ 4.0 %) with an absolute matrix factor between 0.89 and 1.00 for all biomatrices. DNDI-6174 was stable under various conditions, including under tissue homogenization conditions, in all biomatrices investigated. This method was successfully applied in a translational study using a murine cutaneous leishmaniasis skin infection model to assess the target site pharmacokinetics of DNDI-6174, supporting its development as clinical candidate.

Place, publisher, year, edition, pages
Elsevier, 2025
Keywords
DNDI-6174, UPLC-MS/MS, Target site pharmacokinetics, Leishmaniasis, Murine tissues
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-559512 (URN)10.1016/j.jchromb.2025.124652 (DOI)001500843600001 ()40413822 (PubMedID)2-s2.0-105005753948 (Scopus ID)
Funder
Swedish Research Council, 2022-01251
Available from: 2025-06-16 Created: 2025-06-16 Last updated: 2025-06-16Bibliographically approved
Dorlo, T. P. C. & Chu, W.-Y. (2025). Skin pharmacokinetics of miltefosine in the treatment of post-kala-azar dermal leishmaniasis in South Asia: authors' response [Letter to the editor]. Journal of Antimicrobial Chemotherapy, 80(4), 1162-1164
Open this publication in new window or tab >>Skin pharmacokinetics of miltefosine in the treatment of post-kala-azar dermal leishmaniasis in South Asia: authors' response
2025 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 80, no 4, p. 1162-1164Article in journal, Letter (Other academic) Published
Place, publisher, year, edition, pages
Oxford University Press, 2025
National Category
Pharmaceutical Sciences Infectious Medicine Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:uu:diva-557533 (URN)10.1093/jac/dkaf059 (DOI)001440256200001 ()40036560 (PubMedID)2-s2.0-105001977473 (Scopus ID)
Available from: 2025-05-28 Created: 2025-05-28 Last updated: 2025-05-28Bibliographically approved
Ramisetty, B. S., Yang, S., Dorlo, T. P. .. & Wang, M. Z. (2024). Determining tissue distribution of the oral antileishmanial agent miltefosine: a physiologically-based pharmacokinetic modeling approach. Antimicrobial Agents and Chemotherapy, 68(7)
Open this publication in new window or tab >>Determining tissue distribution of the oral antileishmanial agent miltefosine: a physiologically-based pharmacokinetic modeling approach
2024 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 68, no 7Article in journal (Refereed) Published
Abstract [en]

Miltefosine (MTS) is the only approved oral drug for treating leishmaniasis caused by intracellular Leishmania parasites that localize in macrophages of the liver, spleen, skin, bone marrow, and lymph nodes. MTS is extensively distributed in tissues and has prolonged elimination half-lives due to its high plasma protein binding, slow metabolic clearance, and minimal urinary excretion. Thus, understanding and predicting the tissue distribution of MTS help assess therapeutic and toxicologic outcomes of MTS, especially in special populations, e.g., pediatrics. In this study, a whole-body physiologically-based pharmacokinetic (PBPK) model of MTS was built on mice and extrapolated to rats and humans. MTS plasma and tissue concentration data obtained by intravenous and oral administration to mice were fitted simultaneously to estimate model parameters. The resulting high tissue-to-plasma partition coefficient values corroborate extensive distribution in all major organs except the bone marrow. Sensitivity analysis suggests that plasma exposure is most susceptible to changes in fraction unbound in plasma. The murine oral-PBPK model was further validated by assessing overlay of simulations with plasma and tissue profiles obtained from an independent study. Subsequently, the murine PBPK model was extrapolated to rats and humans based on species-specific physiological and drug-related parameters, as well as allometrically scaled parameters. Fold errors for pharmacokinetic parameters were within acceptable range in both extrapolated models, except for a slight underprediction in the human plasma exposure. These animal and human PBPK models are expected to provide reliable estimates of MTS tissue distribution and assist dose regimen optimization in special populations.

Place, publisher, year, edition, pages
American Society for Microbiology, 2024
Keywords
leishmaniasis, physiologically-based pharmacokinetic modeling (PBPK), miltefosine, tissue distribution, pharmacometrics, interspecies extrapolation
National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-542138 (URN)10.1128/aac.00328-24 (DOI)001239606000001 ()38842325 (PubMedID)
Available from: 2024-11-08 Created: 2024-11-08 Last updated: 2024-11-08Bibliographically approved
Schouten, W. M., Roseboom, I. C., Lucas, L., Tshiongo, J. K., Mavoko, H. M., Kayentao, K., . . . Dorlo, T. (2024). Development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry method for the quantification of the antimalarial drug pyronaridine in human whole blood. Journal of Pharmaceutical and Biomedical Analysis, 245, Article ID 116154.
Open this publication in new window or tab >>Development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry method for the quantification of the antimalarial drug pyronaridine in human whole blood
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2024 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 245, article id 116154Article in journal (Refereed) Published
Abstract [en]

Malaria remains a major health concern, aggravated by emerging resistance of the parasite to existing treatments. The World Health Organization recently endorsed the use of artesunate-pyronaridine to treat uncomplicated malaria. However, there is a lack of clinical pharmacokinetic (PK) data of pyronaridine, particularly in special populations such as children and pregnant women. Existing methods for the quantification of pyronaridine in biological matrices to support PK studies exhibit several drawbacks. These include limited sensitivity, a large sample volume required, and extensive analysis time. To overcome these limitations, an ultra-performance reversed-phase liquid chromatography tandem-mass spectrometry method to determine pyronaridine was developed and validated according to international guidelines. The method enabled fast and accurate quantification of pyronaridine in whole blood across a clinically relevant concentration range of 0.500-500 ng/mL (r2 >= 0.9963), with a required sample volume of 50 mu L. Pyronaridine was extracted from whole blood using liquidliquid extraction, effectively eliminating the matrix effect and preventing ion enhancement or suppression. The method achieved a satisfactory reproducible sample preparation recovery of 77%, accuracy (as bias) and precision were within +/- 8.2% and <= 5.3%, respectively. Stability experiments demonstrated that pyronaridine was stable for up to 315 days when stored at - 70 degrees C. Adjustments to the chromatographic system substantially reduced carry-over and improved sensitivity compared to prior methods. The method was successfully applied to quantify pyronaridine in whole blood samples from a selection of pregnant malaria patients participating in the PYRAPREG clinical trial (PACTR202011812241529) in the Democratic Republic of the Congo, demonstrating its suitability to support future PK studies. Furthermore, the enhanced sensitivity allows for the determination of pyronaridine up to 42 days post-treatment initiation, enabling assessment of the terminal elimination half-life.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Pyronaridine, UPLC-MS/MS, Whole blood, Pharmacokinetics, Liquid-liquid extraction
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-531105 (URN)10.1016/j.jpba.2024.116154 (DOI)001234767000001 ()38657367 (PubMedID)
Funder
Swedish Research Council, 2022-01251
Available from: 2024-06-11 Created: 2024-06-11 Last updated: 2024-06-11Bibliographically approved
Chu, W.-Y., Verrest, L., Younis, B. M., Musa, A. M., Mbui, J., Mohammed, R., . . . Dorlo, T. P. .. (2024). Disease-Specific Differences in Pharmacokinetics of Paromomycin and Miltefosine Between Post-Kala-Azar Dermal Leishmaniasis and Visceral Leishmaniasis Patients in Eastern Africa. Journal of Infectious Diseases, 230(6), e1375-e1384
Open this publication in new window or tab >>Disease-Specific Differences in Pharmacokinetics of Paromomycin and Miltefosine Between Post-Kala-Azar Dermal Leishmaniasis and Visceral Leishmaniasis Patients in Eastern Africa
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2024 (English)In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 230, no 6, p. e1375-e1384Article in journal (Refereed) Published
Abstract [en]

Treatment regimens for post-kala-azar dermal leishmaniasis (PKDL) are usually extrapolated from those for visceral leishmaniasis (VL), but drug pharmacokinetics (PK) can differ due to disease-specific variations in absorption, distribution, and elimination. This study characterized PK differences in paromomycin and miltefosine between 109 PKDL and 264 VL patients from eastern Africa. VL patients showed 0.55-fold (95%CI: 0.41-0.74) lower capacity for paromomycin saturable reabsorption in renal tubules, and required a 1.44-fold (1.23-1.71) adjustment when relating renal clearance to creatinine-based eGFR. Miltefosine bioavailability in VL patients was lowered by 69% (62-76) at treatment start. Comparing PKDL to VL patients on the same regimen, paromomycin plasma exposures were 0.74-0.87-fold, while miltefosine exposure until the end of treatment day was 1.4-fold. These pronounced PK differences between PKDL and VL patients in eastern Africa highlight the challenges of directly extrapolating dosing regimens from one leishmaniasis presentation to another.Keywords: Miltefosine; Paromomycin; Pharmacokinetics; Post-kala-azar dermal leishmaniasis (PKDL); Visceral leishmaniasis (VL).

Place, publisher, year, edition, pages
Oxford University Press, 2024
Keywords
paromomycin, miltefosine, post-kala-azar dermal leishmaniasis, visceral leishmaniasis, pharmacokinetics
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-545195 (URN)10.1093/infdis/jiae413 (DOI)001303488500001 ()39166299 (PubMedID)
Funder
European Commission, RIA2016S-1635Swedish Research Council, 2022–01251
Available from: 2024-12-12 Created: 2024-12-12 Last updated: 2024-12-17Bibliographically approved
Damoiseaux, D., Beijnen, J. H., Huitema, A. D. R. & Dorlo, T. P. C. (2024). Early Prediction and Impact Assessment of CYP3A4-Related Drug-Drug Interactions for Small-Molecule Anticancer Drugs Using Human-CYP3A4-Transgenic Mouse Models. Drug Metabolism And Disposition, 52(11), 1217-1223
Open this publication in new window or tab >>Early Prediction and Impact Assessment of CYP3A4-Related Drug-Drug Interactions for Small-Molecule Anticancer Drugs Using Human-CYP3A4-Transgenic Mouse Models
2024 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 52, no 11, p. 1217-1223Article in journal (Refereed) Published
Abstract [en]

Early detection of drug-drug interactions (DDIs) can facilitate timely drug development decisions, prevent unnecessary restrictions on patient enrollment, resulting in clinical study populations that are not representative of the indicated study population, and allow for appropriate dose adjustments to ensure safety in clinical trials. All of these factors contribute to a streamlined drug approval process and enhanced patient safety. Here we describe a new approach for early prediction of the magnitude of change in exposure for cytochrome P450 (P450) CYP3A4-related DDIs of small- molecule anticancer drugs based on the model-based extrapolation of human-CYP3A4-transgenic mice pharmacokinetics to humans. Victim drugs brigatinib and lorlatinib were evaluated with the new approach in combination with the perpetrator drugs itraconazole and rifampicin. Predictions of the magnitude of change in exposure deviated at most 0.99- to 1.31-fold from clinical trial results for inhibition with itraconazole, whereas exposure predictions for the induction with rifampicin were less accurate, with deviations of 0.22- to 0.48-fold. Results for the early prediction of DDIs and their clinical impact appear promising for CYP3A4 inhibition, but validation with more victim and perpetrator drugs is essential to evaluate the performance of the new method.

SIGNIFICANCE STATEMENT

The described method offers an alternative for the early detection and assessment of potential clinical impact of CYP3A4-related drug-drug interactions. The model was able to adequately describe the inhibition of CYP3A4 metabolism and the subsequent magnitude of change in exposure. However, it was unable to accurately predict the magnitude of change in exposure of victim drugs in combination with an inducer.

Place, publisher, year, edition, pages
American Society for Pharmacology & Experimental Therapeutics (ASPET), 2024
National Category
Pharmacology and Toxicology Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-542799 (URN)10.1124/dmd.123.001530 (DOI)001339450000011 ()39362699 (PubMedID)
Available from: 2024-11-15 Created: 2024-11-15 Last updated: 2024-11-15Bibliographically approved
Verrest, L., Monnerat, S., Musa, A. M., Mbui, J., Khalil, E. A. G., Olobo, J., . . . Dorlo, T. (2024). Leishmania blood parasite dynamics during and after treatment of visceral leishmaniasis in Eastern Africa: A pharmacokinetic-pharmacodynamic model. PLoS Neglected Tropical Diseases, 18(4), Article ID e0012078.
Open this publication in new window or tab >>Leishmania blood parasite dynamics during and after treatment of visceral leishmaniasis in Eastern Africa: A pharmacokinetic-pharmacodynamic model
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2024 (English)In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 18, no 4, article id e0012078Article in journal (Refereed) Published
Abstract [en]

Background: With the current treatment options for visceral leishmaniasis (VL), recrudescence of the parasite is seen in a proportion of patients. Understanding parasite dynamics is crucial to improving treatment efficacy and predicting patient relapse in cases of VL. This study aimed to characterize the kinetics of circulating Leishmania parasites in the blood, during and after different antileishmanial therapies, and to find predictors for clinical relapse of disease.

Methods: Data from three clinical trials, in which Eastern African VL patients received various antileishmanial regimens, were combined in this study. Leishmania kinetoplast DNA was quantified in whole blood with real-time quantitative PCR (qPCR) before, during, and up to six months after treatment. An integrated population pharmacokinetic-pharmacodynamic model was developed using non-linear mixed effects modelling.

Results: Parasite proliferation was best described by an exponential growth model, with an in vivo parasite doubling time of 7.8 days (RSE 12%). Parasite killing by fexinidazole, liposomal amphotericin B, sodium stibogluconate, and miltefosine was best described by linear models directly relating drug concentrations to the parasite elimination rate. After treatment, parasite growth was assumed to be suppressed by the host immune system, described by an Emax model driven by the time after treatment. No predictors for the high variability in onset and magnitude of the immune response could be identified. Model-based individual predictions of blood parasite load on Day 28 and Day 56 after start of treatment were predictive for clinical relapse of disease.

Conclusion: This semi-mechanistic pharmacokinetic-pharmacodynamic model adequately captured the blood parasite dynamics during and after treatment, and revealed that high blood parasite loads on Day 28 and Day 56 after start of treatment are an early indication for VL relapse, which could be a useful biomarker to assess treatment efficacy of a treatment regimen in a clinical trial setting.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2024
National Category
Pharmaceutical Sciences Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-527489 (URN)10.1371/journal.pntd.0012078 (DOI)001207176100001 ()38640118 (PubMedID)
Available from: 2024-05-08 Created: 2024-05-08 Last updated: 2024-05-08Bibliographically approved
Projects
Precision medicine tools for the neglected tropical disease visceral leishmaniasis [2022-01251_VR]; Uppsala University; Publications
Schouten, W. M., Van Bocxlaer, K., Rosing, H., Huitema, A. D. R., Beijnen, J. H., Kratz, J. M., . . . Dorlo, T. P. C. (2025). Quantitative analysis of DNDI-6174 using UPLC-MS/MS: A preclinical target site pharmacokinetic study. Journal of chromatography. B, 1262, Article ID 124652.
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-3076-8435

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