| 1. |
- Chu, Wan-Yu, et al.
(författare)
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Pharmacokinetic/Pharmacodynamic Modelling of Allopurinol, its Active Metabolite Oxypurinol, and Biomarkers Hypoxanthine, Xanthine and Uric Acid in Hypoxic-Ischemic Encephalopathy Neonates
- 2022
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Ingår i: Clinical Pharmacokinetics. - : Springer Nature. - 0312-5963 .- 1179-1926. ; 61:2, s. 321-333
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Tidskriftsartikel (refereegranskat)abstract
- 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 of the current study was to establish the pharmacokinetics (PK) of allopurinol and oxypurinol, and the pharmacodynamics (PD) of both compounds on hypoxanthine, xanthine, and uric acid in HIE neonates. The dosage used and the effect of allopurinol in this population, either or not undergoing therapeutic hypothermia (TH), were evaluated.METHODS: Forty-six neonates from the ALBINO study and two historical clinical studies were included. All doses were administered on the first day of life. In the ALBINO study (n = 20), neonates received a first dose of allopurinol 20 mg/kg, and, in the case of TH (n = 13), a second dose of allopurinol 10 mg/kg. In the historical cohorts (n = 26), neonates (all without TH) received two doses of allopurinol 20 mg/kg in total. Allopurinol and oxypurinol population PK, and their effects on inhibiting conversions of hypoxanthine and xanthine to uric acid, were assessed using nonlinear mixed-effects modelling.RESULTS: Allopurinol and oxypurinol PK were described by two sequential one-compartment models with an autoinhibition effect on allopurinol metabolism by oxypurinol. For allopurinol, clearance (CL) was 0.83 L/h (95% confidence interval [CI] 0.62-1.09) and volume of distribution (Vd) was 2.43 L (95% CI 2.25-2.63). For metabolite oxypurinol, CL and Vd relative to a formation fraction (fm) were 0.26 L/h (95% CI 0.23-0.3) and 11 L (95% CI 9.9-12.2), respectively. No difference in allopurinol and oxypurinol CL was found between TH and non-TH patients. The effect of allopurinol and oxypurinol on XO inhibition was described by a turnover model of hypoxanthine with sequential metabolites xanthine and uric acid. The combined allopurinol and oxypurinol concentration at the half-maximal XO inhibition was 0.36 mg/L (95% CI 0.31-0.42).CONCLUSION: The PK and PD of allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid in neonates with HIE were described. The dosing regimen applied in the ALBINO trial leads to the targeted XO inhibition in neonates treated with or without TH.
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| 2. |
- Palic, Semra, et al.
(författare)
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Skin pharmacokinetics of miltefosine in the treatment of post-kala-azar dermal leishmaniasis in South Asia
- 2024
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 79:7, s. 1547-1554
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Post-kala-azar dermal leishmaniasis (PKDL) arises as a dermal complication following a visceral leishmaniasis (VL) infection. Current treatment options for PKDL are unsatisfactory, and there is a knowledge gap regarding the distribution of antileishmanial compounds within human skin. The present study investigated the skin distribution of miltefosine in PKDL patients, with the aim to improve the understanding of the pharmacokinetics at the skin target site in PKDL.Methods: Fifty-two PKDL patients underwent treatment with liposomal amphotericin B (20mg/kg) plus miltefosine (allometric dosing) for 21 days. Plasma concentrations of miltefosine were measured on study days 8, 15, 22 and 30, while a punch skin biopsy was taken on day 22. A physiologically based pharmacokinetic (PBPK) model was developed to evaluate the distribution of miltefosine into the skin.Results: Following the allometric weight-based dosing regimen, median miltefosine concentrations on day 22 were 43.73 mu g/g (IQR: 21.94-60.65 mu g/g) in skin and 33.29 mu g/mL (IQR: 25.9-42.58 mu g/mL) in plasma. The median individual concentration ratio of skin to plasma was 1.19 (IQR: 0.79-1.9). In 87% (45/52) of patients, skin exposure was above the suggested EC90 PK target of 10.6mg/L associated with in vitro susceptibility. Simulations indicated that the residence time of miltefosine in the skin would be more than 2-fold longer than in plasma, estimated by a mean residence time of 604 versus 266 hours, respectively.Conclusion: This study provides the first accurate measurements of miltefosine penetration into the skin, demonstrating substantial exposure and prolonged retention of miltefosine within the skin. These findings support the use of miltefosine in cutaneous manifestations of leishmaniasis. In combination with parasitological and clinical data, these results are critical for the future optimization of combination therapies with miltefosine in the treatment of PKDL.
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| 3. |
- Schmidt, Keith T, et al.
(författare)
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Population pharmacokinetic analysis of nanoparticle-bound and free camptothecin after administration of NLG207 in adults with advanced solid tumors.
- 2020
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 86:4, s. 475-486
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Tidskriftsartikel (refereegranskat)abstract
- 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 two phase II clinical trials (NCT02769962 and NCT03531827), dense sampling was performed up to 48 h post-administration of NLG207 during cycle one and six of treatment; samples were also collected at ~ 360 h post-dose. Conjugated and free CPT concentrations were quantified from each sample, resulting in 477 observations to build a popPK model using non-linear mixed-effects modeling.RESULTS: The PK of NLG207 was characterized by combining two linear two-compartment models with first-order kinetics each to describe nanoparticle-bound (conjugated) and free CPT. Allometric scaling based on body weight provided the best body-size descriptor for all PK parameters. The typical volumes of distribution of the conjugated CPT central and free CPT central compartments were 3.16 L (BSV CV%; 18.1%) and 21.1 L (CV%; 79.8%), respectively. CPT release from the nanoparticle formulation was characterized via an initial rapid clearance of 5.71 L/h (CV%; 62.6%), which decreased via first-order decay (estimated half-life of 0.307 h) to the steady-state value of 0.0988 L/h (CV%; 33.5%) by ~ 4 h after end of infusion. Renal clearance of free CPT was 0.874 L/h (CV%; 42.2%).CONCLUSION: The popPK model confirmed nanoparticle behavior of conjugated CPT and mechanistically characterized CPT release from NLG207. The current analysis provides a strong foundation for future study as a potential predictive tool in ongoing NLG207 clinical trials.
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| 4. |
- Verrest, Luka, et al.
(författare)
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Leishmania blood parasite dynamics during and after treatment of visceral leishmaniasis in Eastern Africa : A pharmacokinetic-pharmacodynamic model
- 2024
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Ingår i: PLoS Neglected Tropical Diseases. - : Public Library of Science (PLoS). - 1935-2727 .- 1935-2735. ; 18:4
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Boosman, René J, et al.
(författare)
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Toxicity of pemetrexed during renal impairment explained-Implications for safe treatment
- 2021
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 149:8, s. 1576-1584
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Tidskriftsartikel (refereegranskat)abstract
- 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 relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m2 would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic-equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13-fold lower area under the concentration-time curve. The pemetrexed exposure-toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment.
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| 6. |
- Chu, Wan-Yu, et al.
(författare)
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Semi-mechanistic Modeling of Hypoxanthine, Xanthine, and Uric Acid Metabolism in Asphyxiated Neonates
- 2022
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Ingår i: Clinical Pharmacokinetics. - : Springer Nature. - 0312-5963 .- 1179-1926. ; 61:11, s. 1545-1558
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Tidskriftsartikel (refereegranskat)abstract
- 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 not be elucidated in our previous study. The current study included additional data from the ALBINO study (NCT03162653) placebo group, aiming to characterize the dynamics of hypoxanthine, xanthine, and uric acid in neonates with hypoxic-ischemic encephalopathy.Methods: Neonates from the ALBINO study who received allopurinol or placebo mannitol were included. An extended population pharmacokinetic-pharmacodynamic model was developed based on the mechanism of purine metabolism, where synthesis, salvage, and degradation via xanthine oxidoreductase pathways were described. The initial level of the biomarkers was a combination of endogenous turnover and high disease-related amounts. Model development was accomplished by nonlinear mixed-effects modeling (NONMEM®, version 7.5).Results: In total, 20 neonates treated with allopurinol and 17 neonates treated with mannitol were included in this analysis. Endogenous synthesis of the biomarkers reduced with 0.43% per hour because of precursor exhaustion. Hypoxanthine was readily salvaged or degraded to xanthine with rate constants of 0.5 1/h (95% confidence interval 0.33-0.77) and 0.2 1/h (95% confidence interval 0.09-0.31), respectively. A greater salvage was found in the allopurinol treatment group consistent with its mechanism of action. High hypoxia-induced initial levels of biomarkers were quantified, and were 1.2-fold to 2.9-fold higher in neonates with moderate-to-severe hypoxic-ischemic encephalopathy compared with those with mild hypoxic-ischemic encephalopathy. Half-maximal xanthine oxidoreductase inhibition was achieved with a combined allopurinol and oxypurinol concentration of 0.68 mg/L (95% confidence interval 0.48-0.92), suggesting full xanthine oxidoreductase inhibition during the period studied.Cconclusions: This extended pharmacokinetic-pharmacodynamic model provided an adequate description of the complex hypoxanthine, xanthine, and uric acid metabolism in neonates with hypoxic-ischemic encephalopathy, suggesting a positive allopurinol effect on these biomarkers. The impact of hypoxia on their dynamics was characterized, underlining higher hypoxia-related initial exposure with a more severe hypoxic-ischemic encephalopathy status.
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| 7. |
- Damoiseaux, David, et al.
(författare)
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Physiologically‐based pharmacokinetic model to predict doxorubicin and paclitaxel exposure in infants through breast milk
- 2023
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Ingår i: CPT. - : John Wiley & Sons. - 2163-8306. ; 12:12, s. 1931-1944
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Tidskriftsartikel (refereegranskat)abstract
- Limited information is available concerning infant exposure and safety when breastfed by mothers receiving chemotherapy. Whereas defining distribution to breast milk is important to infer drug exposure, infant pharmacokinetics also determine to what extent the infant will be exposed to potential toxic effects. We aimed to assess the impact of chemotherapy containing breast milk on infants by predicting systemic and local (intestinal) exposure of paclitaxel and doxorubicin in infants through breast milk using a physiologically-based pharmacokinetic (PBPK) approach. Whole-body PBPK models of i.v. paclitaxel and doxorubicin were extended from the literature, with an oral absorption component to enable predictions in infants receiving paclitaxel or doxorubicin-containing breast milk. For safety considerations, worst-case scenarios were explored. Finally, paclitaxel and doxorubicin exposures in plasma and intestinal tissue of infants following feeding of breast milk from paclitaxel- or doxorubicin-treated mothers were simulated and breast milk discarding strategies were evaluated. The upper 95th percentile of the predicted peak concentrations in peripheral venous blood were 3.48 and 0.74 nM (0.4%–1.7% and 0.1%–1.8% of on-treatment) for paclitaxel and doxorubicin, respectively. Intestinal exposure reached peak concentrations of 1.0 and 140 μM for paclitaxel and doxorubicin, respectively. Discarding breast milk for the first 3 days after maternal chemotherapy administration reduced systemic and tissue exposures even further, to over 90% and 80% for paclitaxel and doxorubicin, respectively. PBPK simulations of chemotherapy exposure in infants after breastfeeding with chemotherapy containing breast milk suggest that particularly local gastrointestinal adverse events should be monitored, whereas systemic adverse events are not expected.
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| 8. |
- Damoiseaux, David, et al.
(författare)
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Population Pharmacokinetic Modelling to Support the Evaluation of Preclinical Pharmacokinetic Experiments with Lorlatinib
- 2022
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier. - 0022-3549 .- 1520-6017. ; 111:2, s. 495-504
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Tidskriftsartikel (refereegranskat)abstract
- 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), which has limitations such as not being able to identify the PK parameter that is affected by the genetic modification of the enzymes or transporters and the requirement of intense and homogeneous sampling of all subjects. Here we used a compartmental population pharmacokinetic modeling approach using PK data from a series of genetically modified mouse experiments with lorlatinib to extend the results and conclusions from previously reported NCA analyses. A compartmental population pharmacokinetic model was built and physiologically plausible covariates were evaluated for the different mouse strains. With the model, similar effects of the strains on the area under the concentration-time curve (AUC) from 0 to 8 hours were found as for the NCA. Additionally, the differences in AUC between the strains were explained by specific effects on clearance and bioavailability for the strain with human expressing CYP3A4. Finally, effects of multidrug efflux transporters ATP-binding cassette (ABC) sub-family B member 1 (ABCB1) and G member 2 (ABCG2) on brain efflux were quantified. Use of compartmental population PK modeling yielded additional insight into the role of drug-metabolizing enzymes and drug transporters in mouse experiments compared to the NCA. Furthermore, these models allowed analysis of heterogeneous pooled datasets and the sparse organ concentration data in contrast to classical NCA analyses.
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| 9. |
- Damoiseaux, David, et al.
(författare)
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Predictability of human exposure by human-CYP3A4-transgenic mouse models : A meta-analysis
- 2024
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Ingår i: Clinical and Translational Science. - : WILEY. - 1752-8054 .- 1752-8062. ; 17:1
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Forskningsöversikt (refereegranskat)abstract
- First-in-human dose predictions are primarily based on no-observed-adverse-effect levels in animal studies. Predictions from these animal models are only as effective as their ability to predict human results. To narrow the gap between human and animals, researchers have, among other things, focused on the replacement of animal cytochrome P450 (CYP) enzymes with their human counterparts (called humanization), especially in mice. Whereas research in humanized mice is extensive, the emphasis has been particularly on qualitative rather than quantitative predictions. Because the CYP3A4 enzyme is most involved in the metabolism of clinically used drugs, most benefit was expected from CYP3A4 models. There are several applications of these mouse models regarding in vivo CYP3A4 functionality, one of which might be their capacity to help improve first-in-human (FIH) dose predictions for CYP3A4-metabolized drugs. To evaluate whether human-CYP3A4-transgenic mouse models are better predictors of human exposure compared to the wild-type mouse model, we performed a meta-analysis comparing both mouse models in their ability to accurately predict human exposure of small-molecule drugs metabolized by CYP3A4. Results showed that, in general, the human-CYP3A4-transgenic mouse model had similar accuracy in the prediction of human exposure compared to the wild-type mouse model, suggesting that there is limited added value in humanization of the mouse Cyp3a enzymes if the primary aim is to acquire more accurate FIH dose predictions. Despite the results of this meta-analysis, corrections for interspecies differences through extension of human-CYP3A4-transgenic mouse models with pharmacokinetic modeling approaches seems a promising contribution to more accurate quantitative predictions of human pharmacokinetics.
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| 10. |
- Damoiseaux, David, et al.
(författare)
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Predicting Chemotherapy Distribution into Breast Milk for Breastfeeding Women Using a Population Pharmacokinetic Approach
- 2023
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Ingår i: Clinical Pharmacokinetics. - : Springer Nature. - 0312-5963 .- 1179-1926. ; 62:7, s. 969-980
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Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectiveInformation on the distribution of chemotherapeutic drugs to breast milk is scarce, and reports are limited to small sample sizes. Anecdotal pharmacokinetic data have typically been acquired from lactating but non-breastfeeding patients who collect breast milk by means of an expression pump, which might not necessarily be representative for a breastfeeding population due to differences in milk production. Consequently, little is known about the variability of chemotherapy distribution to breast milk and the effect of milk production on the distribution of chemotherapy to breast milk. Our aim was to predict chemotherapy distribution to breast milk in a more realistic breastfeeding population and evaluate the effect of discarding breast milk on the potential chemotherapy exposure in infants.MethodsWe developed a population pharmacokinetic model that described the breast milk production and the chemotherapy distribution to breast milk of a non-breastfeeding population, linked it to plasma pharmacokinetics, and extrapolated this to a breastfeeding population.ResultsWe found that cumulative relative infant doses (RID) were higher than 10% for cyclophosphamide and doxorubicin and approximately 1% for paclitaxel. Simulations allowed us to predict the cumulative RID and its variability in the population for patients with different milk productions and the amount of breast milk that has to be discarded to reach cumulative RIDs below 1%, 0.1%, and 0.01%. Discarding 1–2, 3–6, and 0–1 days of breast milk (depending on the milk production of the patient) resulted in cumulative RID below 1% for cyclophosphamide, doxorubicin, and paclitaxel, respectively.ConclusionOur results may help clinicians to derive the optimal breast milk discarding strategy for an individual patient that wants to breastfeed during chemotherapy and minimize chemotherapy exposure in their infants.
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