Thomas Dorlo

Uppsala University | UU · Department of Pharmacy

Background: Recent studies have reported ethnic differences in vincristine exposure and outcomes such as toxicity. This resulted in the hypothesis of subtherapeutic dosing in African children. To optimize individual treatment, a strategy to identify subtherapeutic exposure using therapeutic drug monitoring is essential. The aim of the current stud...

Studies to evaluate and optimize [177 Lu]Lu-PSMA treatment focus primarily on individual patient data. A population pharmacokinetic (PK) dosimetry model was developed to explore the potential of using imaging data as input for population PK models and to characterize variability in organ and tumor uptake of [177 Lu]Lu-PSMA-617 in patients with low...

Background Little is known about parameters that have a relevant impact on (dis)similarities in biodistribution between various ⁶⁸Ga-labeled somatostatin analogues. Additionally, the effect of tumor burden on organ uptake remains unclear. Therefore, the aim of this study was to describe and compare organ and tumor distribution of [⁶⁸Ga]Ga-DOTATATE...

Microdosing is a strategy to obtain knowledge of human pharmacokinetics prior to Phase I clinical trials. The most frequently used method to extrapolate microdose (≤100 μg) pharmacokinetics to therapeutic doses is based on linear extrapolation from a noncompartmental analysis (NCA) with a two-fold acceptance criterion between pharmacokinetic metric...

BACKGROUND AND OBJECTIVE Previously, we developed a pharmacokinetic-pharmacodynamic model of allopurinol, oxypurinol, and biomarkers, hypoxanthine, xanthine, and uric acid, in neonates with hypoxic-ischemic encephalopathy, in which high initial biomarker levels were observed suggesting an impact of hypoxia. However, the full pharmacodynamics could...

Bioanalytical assay development and validation procedures were performed to quantify antiprotozoal drug paromomycin in human skin tissue by ultra-high performance liquid chromatography coupled to tandem mass spectrometry. Paromomycin, an aminoglycoside drug, is administered intra-muscularly and used in the treatment of multiple clinical presentatio...

Bioanalytical method development and validation for the quantification of antileishmanial drugs are pivotal to support clinical trials and provide the data necessary to conduct pharmacokinetic analysis. This review provides a comprehensive overview of published validated bioanalytical assays for the quantification of antileishmanial drugs amphoteri...

Background This study aimed to determine whether paromomycin plus miltefosine (PM/MF) is noninferior to sodium stibogluconate plus paromomycin (SSG/PM) for treatment of primary visceral leishmaniasis in eastern Africa. Methods An open-label, phase 3, randomized, controlled trial was conducted in adult and pediatric patients at 7 sites in eastern A...

Background and Objective Previously, we developed a pharmacokinetic-pharmacodynamic model of allopurinol, oxypurinol, and biomarkers, hypoxanthine, xanthine, and uric acid, in neonates with hypoxic-ischemic encephalopathy, in which high initial biomarker levels were observed suggesting an impact of hypoxia. However, the full pharmacodynamics could...

The extrapolation of drug exposure between species remains a challenging step in drug development, contributing to the low success rate of drug approval. As a consequence, extrapolation of toxicology from animal models to humans to evaluate safe, first-in-human (FIH) doses requires high safety margins. We hypothesized that a human-CYP3A4-expressing...

Correlations between increasing concentrations of circulating tumor DNA (ctDNA) in plasma and disease progression have been shown. A nonlinear mixed effects model to describe the dynamics of epidermal growth factor receptor (EGFR) ctDNA data from patients with non‐small cell lung cancer (NSCLC) combined with a parametric survival model were develop...

Amphotericin B is an antifungal and antiparasitic drug used in first-line treatment of the parasitic neglected tropical disease leishmaniasis. Liposomal amphotericin B is currently studied for the treatment of cutaneous and post-kala-azar dermal leishmaniasis, where the dermis of the skin is infected with Leishmania parasites. For the optimization...

Purpose Orally administered paclitaxel offers increased patient convenience while providing a method to prolong exposure without long continuous, or repeated, intravenous infusions. The oral bioavailability of paclitaxel is improved through co-administration with ritonavir and application of a suitable pharmaceutical formulation, which addresses th...

Little is known about infant’s safety of chemotherapy during breastfeeding where evidence is limited to few case reports. This lack of knowledge has led to a general tendency to advice against breastfeeding during cytotoxic therapy despite the overwhelming benefits that breastfeeding offers to both the mother and their children. In this case series...

Background: Most cancer patients treated with everolimus experience stomatitis, which seriously affects the quality of life. The salivary concentrations of everolimus may predict the incidence and severity of stomatitis. The authors aimed to examine whether it was feasible to quantify the everolimus concentration in saliva and subsequently use it...

Background: Allopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE). Currently, a double-blind, placebo-controlled study (ALBINO, NCT03162653) is investigating the neuroprotective effect of allopurinol in HIE neonates. Objective: The aim...

Miltefosine is an alkylphosphocholine agent with a broad spectrum of antiparasitic properties. For over two decades now, miltefosine remains the first and only oral drug licensed and used in treatment of the neglected tropical disease leishmaniasis. An extensive review on the pharmacology of miltefosine was last published in 2012, while additional...

The effect of transporters and enzymes on drug pharmacokinetics is increasingly evaluated using genetically modified animals that have these proteins either knocked-out or their human orthologues transgenically expressed. Analysis of pharmacokinetic data obtained in such experiments is typically performed using non-compartmental analysis (NCA), whi...

Miltefosine is the only oral drug approved for the treatment of various clinical presentations of the neglected parasitic disease leishmaniasis. In cutaneous leishmaniasis and post-kala-azar dermal leishmaniasis, Leishmania parasites reside and multiply in the dermis of the skin. As miltefosine is orally administered and this drug is currently stud...

Background Physiologically based pharmacokinetic (PBPK) models combine drug-specific information with prior knowledge on the physiology and biology at the organism level. Whole-body PBPK models contain an explicit representation of the organs and tissue and are a tool to predict pharmacokinetic behavior of drugs . The aim of this study was to devel...

Background A low skeletal muscle mass (SMM) has been associated with increased toxicity and shorter survival in cancer patients treated with capecitabine, an oral prodrug of 5-fluorouracil (5-FU). Capecitabine and its metabolites are highly water-soluble and, therefore, more likely to distribute to lean tissues. The pharmacokinetics (PK) in patient...

IntroductionIntramuscular paromomycin monotherapy to treat visceral leishmaniasis (VL) has been shown to be effective for Indian patients, while a similar regimen resulted in lower efficacy in Eastern Africa, which could be related to differences in paromomycin pharmacokinetics.Methods Pharmacokinetic data were available from two randomized control...

The anticancer drug docetaxel exhibits large interpatient pharmacokinetic and pharmacodynamic variability. In this study, we aimed to assess the functional significance of 14 polymorphisms in the CYP3A, CYP1B1, ABCB1, ABCC2, and SLCO1B3 genes for the pharmacokinetics and pharmacodynamics of oral docetaxel, co-administered with ritonavir. None of th...

Background Patients affected by poverty-related infectious diseases (PRDs) are disproportionally affected by malnutrition. To optimize treatment of patients affected by PRDs, we aimed to assess the influence of malnutrition associated with PRDs on drug pharmacokinetics, by way of a systematic review.MethodsA systematic review was performed on the e...

Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the rela...

Background Despite high HIV co-infection prevalence in Ethiopian visceral leishmaniasis (VL) patients, the adequacy of antileishmanial drug exposure in this population and effect of HIV-VL co-morbidity on pharmacokinetics of antileishmanial and antiretroviral (ARV) drugs is still unknown. Methods HIV-VL co-infected patients received the recommende...

Background: In order to expedite the development of new oral treatment regimens for visceral leishmaniasis (VL), there is a need for early markers to evaluate treatment response and predict long-term outcomes. Methods: Data from three clinical trials were combined in this study, where Eastern African VL patients received various antileishmanial...

Background Based on reassuring short-term foetal and maternal safety data, there is an increasing trend to administer chemotherapy during the second and third trimesters of pregnancy. The pharmacokinetics (PK) of drugs might change as a result of several physiological changes that occur during pregnancy, potentially affecting the efficacy and safet...

Capecitabine is an oral pro-drug of 5-fluorouracil. Patients with solid tumours who are treated with capecitabine may develop hand-and-foot syndrome (HFS) as side effect. This might be a result of accumulation of intracellular metabolites. We characterised the pharmacokinetics (PK) of 5-fluorouridine 5′-triphosphate (FUTP) in peripheral blood monon...

Introduction Oral formulations of docetaxel have successfully been developed as an alternative for intravenous administration. Co-administration with the enzyme inhibitor ritonavir boosts the docetaxel plasma exposure. In dose-escalation trials, the maximum tolerated doses for two different dosing regimens were established and dose-limiting toxicit...

Purpose: NLG207 (formerly CRLX101) is a nanoparticle-drug conjugate (NDC) of the potent topoisomerase I inhibitor, camptothecin (CPT). The present study sought to characterize the complex pharmacokinetics (PK) of NLG207 and better describe CPT release from nanoparticles using a population PK (popPK) model. Methods: From 27 patients enrolled on t...

Background: Conventional miltefosine dosing (2.5 mg/kg/day) for treatment of visceral leishmaniasis (VL) is less effective in children than in adults. A higher allometric dose (median 3.2 mg/kg/day) was therefore investigated in paediatric VL patients in Eastern Africa. Results of this trial showed an unforeseen, lower than dose-proportional incre...

Quantification of pharmaceutical compounds in skin tissue is challenging because of low expected concentrations, small typical sample volumes, and the hard nature of the skin structure itself. This review provides a comprehensive overview of sample collection, sample homogenization and analyte extraction methods that have been used to quantify phar...

Background: For oral anticancer drugs, trough concentration (Cmin) is usually used as a target in therapeutic drug monitoring (TDM). Recording of Cmin is highly challenging in outpatients, in whom there is typically a variability in sample collection time after dosing. Various methods are used to estimate Cmin from the collected samples. This simu...

Op dit moment is er geen middel geregistreerd voor de behandeling van menselijke coronavirusinfecties. Terwijl de ontwikkeling van nieuwe therapeutische interventies onderweg is, wordt nu vol ingezet op het hergebruiken (repurposing) van bestaande middelen. In afwachting van de resultaten van de prospectieve studies, geven we een overzicht van het...

A highly sensitive method was developed to quantitate the antileishmanial agent paromomycin in human plasma, with a lower limit of quantification of 5 ng/mL. Separation was achieved using an isocratic ion-pair ultra-high performance liquid chromatographic (UPLC) method with a minimal concentration of heptafluorobutyric acid, which was coupled throu...

In recent years new targeted small molecule kinase inhibitors (KI) have become available for pediatric patients with cancer. Relationships between drug exposure and treatment response have been established for several of these drugs in adults. Following these exposure‐response relationships, pharmacokinetic (PK) target Cmin values to guide therapeu...

Background and ObjectivesMCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors and is in development to overcome HER3-mediated resistance to anti-HER2 therapies. The aims of this analysis were to characterize the population pharmacokinetics of MCLA-128 in patients with various solid tumors, to evaluate patient-related f...

Optimal fludarabine exposure has been associated with improved treatment outcome in allogeneic hematopoietic cell transplantation (HCT), suggesting potential benefit of individualized dosing. A randomized controlled trial (RCT) comparing alternative fludarabine dosing strategies to current practice may be warranted, but should be sufficiently power...

Background Docetaxel is commonly used in elderly patients, who are frequently diagnosed with prostate cancer. Although previous studies revealed no clinically relevant impact of older age on docetaxel pharmacokinetics (PK), this may be masked by indication. Metastatic castration-resistant prostate cancer (mCRPC) patients were reported to have appro...

Background Miltefosine (Profounda, FL) is an oral alkylphospholipid drug which is approved by the Food and Drug Administration for the treatment of some species of New World cutaneous leishmaniasis. The maximal daily recommended dosage is 50 mg t.i.d for 28 days; yet there is some evidence that doses <2.5 mg/kg/day may be associated with lesser eff...

Purpose There is ongoing concern regarding increased toxicity from paclitaxel in elderly patients, particularly of severe neutropenia. Yet, data so far is controversial and this concern is not supported by a clinically relevant age-dependent difference in pharmacokinetics (PK) of paclitaxel. This study assessed whether age is associated with increa...

Since its founding in 1948, maintenance of the International Classification of Diseases (ICD) report is among the many tasks allocated to the World Health Organization (WHO). The ICD was initially started by the U.S. International Statistical Institute as the International List of Causes of Death. More than 100 countries worldwide use the ICD curre...

Fludarabine is the most frequently used agent in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). Body surface area-based dosing leads to highly variable fludarabine exposure. We studied the relation between fludarabine exposure and clinical outcomes. A retrospective, pharmacokinetic-pharmacodynamic analysis was conduc...

Introduction The pharmacokinetics (PK) of the 20S proteasome inhibitor bortezomib are characterized by a large volume of distribution and a rapid decline in plasma concentrations within the first hour after administration. An increase in exposure was observed in the second week of treatment, which has previously been explained by extensive binding...

Host immune responses are pivotal for the successful treatment of the leishmaniases, a spectrum of infections caused by Leishmania parasites. Previous studies speculated that augmenting cytokines associated with a type 1 T-helper cell (Th1) response is necessary to combat severe forms of leishmaniasis, where it has been hypothesized that the antile...

Door een sterke internationale lobby van de Chinese overheid krijgen ‘geneesmiddelen’ als kruiden en acupunctuur een formele status. Een riskante zaak, waar Nederland zich van moet distantiëren, vinden antikwakzalvers Cees Renckens en Thomas Dorlo.

Purpose Limited available data suggest that older patients are more prone to develop paclitaxel-induced toxicity than their younger peers. It remains unclear whether this is related to age-dependent pharmacokinetics (PK) of paclitaxel. Primary objective of this study was to determine the influence of older age on the PK of paclitaxel. Methods PK d...

Background Fludarabine is often used as an important drug in reduced toxicity conditioning regimens prior to hematopoietic cell transplantation (HCT). As no definitive pharmacokinetic (PK) basis for HCT dosing for the wide age and weight range in HCT is available, linear body surface area (BSA)-based dosing is still used. Objective We sought to de...

Background: Convenient, safe, and effective treatments for visceral leishmaniasis in Eastern African children are lacking. Miltefosine, the only oral treatment, failed to achieve adequate cure rates in Eastern Africa, particularly in children, in whom linear dosing (2.5 mg/kg/day for 28 days) resulted in 59% cure rate, with lower systemic miltefos...

The artemisinin-based combination therapy artemether-lumefantrine is commonly used in pregnant malaria patients. However, the effect of pregnancy-related changes on exposure is unclear and pregnancy has been associated with decreased efficacy in previous studies. This study aimed to characterize the population pharmacokinetics of artemether, its ac...

Trastuzumab is associated with cardiotoxicity, manifesting as a decrease of the left-ventricular ejection fraction (LVEF). Administration of anthracyclines prior to trastuzumab increases risk of cardiotoxicity. High-sensitive troponin T and N-terminal-pro-brain natriuretic peptide (NT-proBNP) are molecular markers that may allow earlier detection o...

The Leishmania parasite resides and replicates within host macrophages during visceral leishmaniasis (VL). This study aimed to evaluate neopterin, a marker of macrophage activation, as possible pharmacodynamic biomarker to monitor VL treatment response and to predict long-term clinical relapse of VL. Following informed consent, 497 plasma samples w...

Objectives: Leishmania parasites reside within macrophages and the direct target of antileishmanial drugs is therefore intracellular. We aimed to characterize the intracellular PBMC miltefosine kinetics by developing a population pharmacokinetic (PK) model simultaneously describing plasma and intracellular PBMC pharmacokinetics. Furthermore, we ex...

Patients with visceral leishmaniasis (VL)–human immunodeficiency virus (HIV) coinfection experience increased drug toxicity and treatment failure rates compared to VL patients, with more frequent VL relapse and death. In the era of VL elimination strategies, HIV coinfection is progressively becoming a key challenge, because HIV-coinfected patients...

For human health, leishmaniasis is among the most important protozoan diseases, superseded only by malaria. Globally, 10 to 12 million people are infected with 1.5 million new cases every year. The development of cheaper new drugs is urgently needed for this neglected disease that is developing resistance to current treatments. Chemotherapy remains...