Publications by authors named "Michiel J van Esdonk"

17 Publications

  • Page 1 of 1

A novel sustained-release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteers.

Pharmacol Res Perspect 2021 Apr;9(2):e00739

Centre for Human Drug Research (CHDR), Leiden, The Netherlands.

The strict intake regimen of cysteamine bitartrate formulations, associated with side effects, is a concern for the treatment compliance in cystinosis therapy. Therefore, there is a need for a cysteamine formulation with an improved pharmacokinetic profile. This study investigated the pharmacokinetics, safety and tolerability of a new sustained-release cysteamine dosage form, PO-001, in healthy volunteers. This was a randomized, investigator-blinded, three-way cross-over study to compare single doses (600 mg) of PO-001 with Cystagon (immediate-release) and Procysbi (delayed-release). Collected blood samples were analyzed for plasma cysteamine concentrations and pharmacokinetic parameters were estimated by noncompartmental analysis. In addition, plasma cysteamine concentrations were analyzed using a population pharmacokinetic approach using NONMEM . Pharmacokinetics showed clear sustained-release characteristics of PO-001 over time with a lower C and longer T compared to Cystagon and Procysbi . All treatment-emergent adverse events were of mild severity, with the exception of two subjects who reported moderate severity gastrointestinal problems including vomiting and diarrhea, which were related to Cystagon intake. Population PK simulations showed a favourable PK profile based on C and C concentrations at steady state. In conclusion, a single dose of 600 mg PO-001 was well tolerated with no findings of clinical concern. This new cysteamine bitartrate formulation showed pharmacokinetics of a sustained-release formulation, which may be beneficial for the treatment of cystinosis patients. This study supports advancing this type of sustained-release formulation into a subsequent study to confirm reduced dosing frequency with efficient control of white blood cells (WBCs) cystine levels. Netherlands Trial Registry (NTR) (NL67638.056.18).
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http://dx.doi.org/10.1002/prp2.739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992283PMC
April 2021

The power of modelling pulsatile profiles.

J Pharmacokinet Pharmacodyn 2021 Mar 3. Epub 2021 Mar 3.

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

The quantitative description of individual observations in non-linear mixed effects models over time is complicated when the studied biomarker has a pulsatile release (e.g. insulin, growth hormone, luteinizing hormone). Unfortunately, standard non-linear mixed effects population pharmacodynamic models such as turnover and precursor response models (with or without a cosinor component) are unable to quantify these complex secretion profiles over time. In this study, the statistical power of standard statistical methodology such as 6 post-dose measurements or the area under the curve from 0 to 12 h post-dose on simulated dense concentration-time profiles of growth hormone was compared to a deconvolution-analysis-informed modelling approach in different simulated scenarios. The statistical power of the deconvolution-analysis-informed approach was determined with a Monte-Carlo Mapped Power analysis. Due to the high level of intra- and inter-individual variability in growth hormone concentrations over time, regardless of the simulated effect size, only the deconvolution-analysis informed approach reached a statistical power of more than 80% with a sample size of less than 200 subjects per cohort. Furthermore, the use of this deconvolution-analysis-informed modelling approach improved the description of the observations on an individual level and enabled the quantification of a drug effect to be used for subsequent clinical trial simulations.
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http://dx.doi.org/10.1007/s10928-021-09743-2DOI Listing
March 2021

Predictive performance of parent-metabolite population pharmacokinetic models of (S)-ketamine in healthy volunteers.

Eur J Clin Pharmacol 2021 Feb 11. Epub 2021 Feb 11.

Centre for Human Drug Research, Leiden, The Netherlands.

Purpose: The recent repurposing of ketamine as treatment for pain and depression has increased the need for accurate population pharmacokinetic (PK) models to inform the design of new clinical trials. Therefore, the objectives of this study were to externally validate available PK models on (S)-(nor)ketamine concentrations with in-house data and to improve the best performing model when necessary.

Methods: Based on predefined criteria, five models were selected from literature. Data of two previously performed clinical trials on (S)-ketamine administration in healthy volunteers were available for validation. The predictive performances of the selected models were compared through visual predictive checks (VPCs) and calculation of the (root) mean (square) prediction errors (ME and RMSE). The available data was used to adapt the best performing model through alterations to the model structure and re-estimation of inter-individual variability (IIV).

Results: The model developed by Fanta et al. (Eur J Clin Pharmacol 71:441-447, 2015) performed best at predicting the (S)-ketamine concentration over time, but failed to capture the (S)-norketamine C correctly. Other models with similar population demographics and study designs had estimated relatively small distribution volumes of (S)-ketamine and thus overpredicted concentrations after start of infusion, most likely due to the influence of circulatory dynamics and sampling methodology. Model predictions were improved through a reduction in complexity of the (S)-(nor)ketamine model and re-estimation of IIV.

Conclusion: The modified model resulted in accurate predictions of both (S)-ketamine and (S)-norketamine and thereby provides a solid foundation for future simulation studies of (S)-(nor)ketamine PK in healthy volunteers after (S)-ketamine infusion.
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http://dx.doi.org/10.1007/s00228-021-03104-1DOI Listing
February 2021

Comprehensive evaluation of microneedle-based intradermal adalimumab delivery vs. subcutaneous administration: results of a randomized controlled clinical trial.

Br J Clin Pharmacol 2021 Jan 5. Epub 2021 Jan 5.

Department of Pediatric Rheumatology Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, the Netherlands.

Aims: To evaluate feasibility of intradermal (i.d.) adalimumab administration using hollow microneedles, and to compare a single i.d. dose of adalimumab using a hollow microneedle with a single subcutaneous (s.c.) dose using a conventional needle.

Methods: In this single-centre double-blind, placebo-controlled, double-dummy clinical trial in 24 healthy adults we compared 40 mg adalimumab (0.4 mL) administered i.d. using a hollow microneedle with a s.c. dose using a conventional needle. Primary parameters were pain, acceptability and local tolerability; secondary parameters safety, pharmacokinetics and immunogenicity. We explored usability of optical coherence tomography, clinical photography, thermal imaging, and laser speckle contrast imaging to evaluate skin reaction after i.d. injections. In vitro protein analysis was performed to assess compatibility of adalimumab with the hollow microneedle device.

Results: While feasible and safe, injection pain of i.d. adalimumab was higher compared to s.c. adalimumab (35.4 vs. 7.9 on a 100-point visual analogue scale). Initial absorption rate and relative bioavailability were higher after i.d. adalimumab (time to maximum plasma concentration = 95 h [47-120]; F = 129% [6.46%]) compared to s.c. adalimumab (time to maximum plasma concentration = 120 h [96-221]). Anti-adalimumab antibodies were detected in 50% and 83% of the subjects after i.d. and s.c. adalimumab, respectively. We observed statistically significantly more erythema and skin perfusion after i.d. adalimumab, compared to s.c. adalimumab and placebo injections (P < .0001). Cytokine secretion after whole blood lipopolysaccharide challenge was comparable between administration routes.

Conclusions: Intradermal injection of adalimumab using hollowing microneedles was perceived as more painful and less accepted than s.c. administration, but yields a higher relative bioavailability with similar safety and pharmacodynamic effects.
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http://dx.doi.org/10.1111/bcp.14729DOI Listing
January 2021

Safety, pharmacokinetics, and pharmacodynamics of Gln-1062, a prodrug of galantamine.

Alzheimers Dement (N Y) 2020 13;6(1):e12093. Epub 2020 Oct 13.

Centre for Human Drug Research Leiden The Netherlands.

Introduction: Gln-1062 (MEMOGAIN) is an intranasally administered lipophilic prodrug of galantamine. Based on high brain-to-blood concentrations observed in pre-clinical studies, Gln-1062 is expected to have superior cognitive efficacy compared to oral galantamine.

Methods: Forty-eight healthy elderly subjects were randomized 12:4 to Gln-1062 (5.5, 11, or 22 mg, b.i.d., for 7 days) or placebo. Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed repeatedly. Pharmacokinetics were compared with 16 mg oral galantamine.

Results: Gln-1062 up to 22 mg, b.i.d., was well tolerated. Gln-1062 plasma concentrations increased immediately following dosing (median T of 0.5 hour [range 0.5-1.0]). C and AUC increased in a dose-linear manner over all three dose levels. Gln-1062 was rapidly cleaved into galantamine. Gln-1062 significantly improved adaptive tracking (sustained attention) with 1.95% (95% confidence interval [CI] 0.630-3.279,  = 0.0055) compared to placebo after correction for individual baseline performance.

Discussion: Gln-1062 was considered to be safe and caused fewer gastrointestinal side effects than oral galantamine. Gln-1062 behaved pharmacokinetically as expected and improved performance on cognitive tests.
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http://dx.doi.org/10.1002/trc2.12093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551138PMC
October 2020

Impact of enantiomer-specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis.

Br J Clin Pharmacol 2021 Mar 9;87(3):1443-1454. Epub 2020 Oct 9.

Intensive Care and Department of Paediatric Surgery, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands.

Aims: Ketorolac is a nonsteroidal anti-inflammatory racemic drug with analgesic effects only attributed to its S-enantiomer. The aim of this study is to quantify enantiomer-specific maturational pharmacokinetics (PK) of ketorolac and investigate if the contribution of both enantiomers to the total ketorolac concentration remains equal between infants and adults or if a change in target racemic concentration should be considered when applied to infants.

Methods: Data were pooled from 5 different studies in adults, children and infants, with 1020 plasma concentrations following single intravenous ketorolac administration. An allometry-based enantiomer-specific population PK model was developed with NONMEM 7.3. Simulations were performed in typical adults and infants to investigate differences in S- and R-ketorolac exposure.

Results: S- and R-ketorolac PK were best described with a 3- and a 2-compartment model, respectively. The allometry-based PK parameters accounted for changes between populations. No maturation function of ketorolac clearance could be identified. All model parameters were estimated with adequate precision (relative standard error <50%). Single dose simulations showed that a previously established analgesic concentration at half maximal effect in adults of 0.37 mg/L, had a mean S-ketorolac concentration of 0.057 mg/L, but a mean S-ketorolac concentration of 0.046 mg/L in infants. To match the effective adult S-ketorolac-concentration (0.057 mg/L) in typical infants, the EC should be increased to 0.41 mg/L.

Conclusion: Enantiomer-specific changes in ketorolac PK yield different concentrations and S- and R-ketorolac ratios between infants and adults at identical racemic concentrations. These PK findings should be considered when studies on maturational pharmacodynamics are considered.
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http://dx.doi.org/10.1111/bcp.14547DOI Listing
March 2021

First-in-Human Assessment of cRGD-ZW800-1, a Zwitterionic, Integrin-Targeted, Near-Infrared Fluorescent Peptide in Colon Carcinoma.

Clin Cancer Res 2020 08 28;26(15):3990-3998. Epub 2020 Apr 28.

Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.

Purpose: Incomplete oncologic resections and damage to vital structures during colorectal cancer surgery increases morbidity and mortality. Moreover, neoadjuvant chemoradiotherapy has become the standard treatment modality for locally advanced rectal cancer, where subsequent downstaging can make identification of the primary tumor more challenging during surgery. Near-infrared (NIR) fluorescence imaging can aid surgeons by providing real-time visualization of tumors and vital structures during surgery.

Experimental Design: We present the first-in-human clinical experience of a novel NIR fluorescent peptide, cRGD-ZW800-1, for the detection of colon cancer. cRGD-ZW800-1 was engineered to have an overall zwitterionic chemical structure and neutral charge to lower nonspecific uptake and thus background fluorescent signal. We performed a phase I study in 11 healthy volunteer as well as a phase II feasibility study in 12 patients undergoing an elective colon resection, assessing 0.005, 0.015, and 0.05 mg/kg cRGD-ZW800-1 for the intraoperative visualization of colon cancer.

Results: cRGD-ZW800-1 appears safe, and exhibited rapid elimination into urine after a single low intravenous dose. Minimal invasive intraoperative visualization of colon cancer through full-thickness bowel wall was possible after an intravenous bolus injection of 0.05 mg/kg at least 2 hours prior to surgery. Longer intervals between injection and imaging improved the tumor-to-background ratio.

Conclusions: cRGD-ZW800-1 enabled fluorescence imaging of colon cancer in both open and minimal invasive surgeries. Further development of cRGD-ZW800-1 for widespread use in cancer surgery may be warranted given the ubiquitous overexpression of various integrins on different types of tumors and their vasculature.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-4156DOI Listing
August 2020

Quantification of the endogenous growth hormone and prolactin lowering effects of a somatostatin-dopamine chimera using population PK/PD modeling.

J Pharmacokinet Pharmacodyn 2020 06 4;47(3):229-239. Epub 2020 Apr 4.

Centre for Human Drug Research, Leiden, The Netherlands.

A phase 1 clinical trial in healthy male volunteers was conducted with a somatostatin-dopamine chimera (BIM23B065), from which information could be obtained on the concentration-effect relationship of the inhibition of pulsatile endogenous growth hormone and prolactin secretion. Endogenous growth hormone profiles were analyzed using a two-step deconvolution-analysis-informed population pharmacodynamic modeling approach, which was developed for the analyses of pulsatile profiles. Prolactin concentrations were modelled using a population pool model with a circadian component on the prolactin release. During treatment with BIM23B065, growth hormone secretion was significantly reduced (maximal effect [E] = - 64.8%) with significant reductions in the pulse frequency in two out of three multiple ascending dose cohorts. A circadian component in prolactin secretion was identified, modelled using a combination of two cosine functions with 24 h and 12 h periods. Dosing of BIM23B065 strongly inhibited (E = - 91%) the prolactin release and demonstrated further reduction of prolactin secretion after multiple days of dosing. This study quantified the concentration-effect relationship of BIM23B065 on the release of two pituitary hormones, providing proof of pharmacology of the chimeric actions of BIM23B065.
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http://dx.doi.org/10.1007/s10928-020-09683-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289785PMC
June 2020

Model informed quantification of the feed-forward stimulation of growth hormone by growth hormone-releasing hormone.

Br J Clin Pharmacol 2020 08 9;86(8):1575-1584. Epub 2020 Mar 9.

Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Aims: Growth hormone (GH) secretion is pulsatile and secretion varies highly between individuals. To understand and ultimately predict GH secretion, it is important to first delineate and quantify the interaction and variability in the biological processes underlying stimulated GH secretion. This study reports on the development of a population nonlinear mixed effects model for GH stimulation, incorporating individual GH kinetics and the stimulation of GH by GH-releasing hormone (GHRH).

Methods: Literature data on the systemic circulation, the median eminence, and the anterior pituitary were included as system parameters in the model. Population parameters were estimated on data from 8 healthy normal weight and 16 obese women who received a 33 μg recombinant human GH dose. The next day, a bolus injection of 100 μg GHRH was given to stimulate GH secretion.

Results: The GH kinetics were best described with the addition of 2 distribution compartments with a bodyweight dependent clearance (increasing linearly from 24.7 L/h for a 60-kg subject to 32.1 L/h for a 100-kg subject). The model described the data adequately with high parameter precision and significant interindividual variability on the GH clearance and distribution volume. Additionally, high variability in the amount of secreted GH, driven by GHRH receptor activation, was identified (coefficient of variation = 90%).

Conclusion: The stimulation of GH by GHRH was quantified and significant interindividual variability was identified on multiple parameters. This model sets the stage for further development of by inclusion of additional physiological components to quantify GH secretion in humans.
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http://dx.doi.org/10.1111/bcp.14265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373696PMC
August 2020

Pharmacokinetics of intravenous and inhaled salbutamol and tobramycin: An exploratory study to investigate the potential of exhaled breath condensate as a matrix for pharmacokinetic analysis.

Br J Clin Pharmacol 2020 01 3;86(1):175-181. Epub 2020 Jan 3.

Centre for Human Drug Research, Leiden, the Netherlands.

Concentrations of drugs acting in the lungs are difficult to measure, resulting in relatively unknown local pharmacokinetics. The aim of this study is to assess the potential of exhaled breath condensate (EBC) as a matrix for pharmacokinetic analysis of inhaled and intravenous medication. A 4-way crossover study was conducted in 12 volunteers with tobramycin and salbutamol intravenously and via inhalation. EBC and plasma samples were collected postdose and analysed for drug concentrations. Sample dilution, calculated using urea concentrations, was used to estimate the epithelial lining fluid concentration. Salbutamol and tobramycin were largely undetectable in EBC after intravenous administration and were detectable after inhaled administration in all subjects in 50.8 and 51.5% of EBC samples, respectively. Correction of EBC concentrations for sample dilution did not explain the high variability. This high variability of EBC drug concentrations seems to preclude EBC as a matrix for pharmacokinetic analysis of tobramycin and salbutamol.
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http://dx.doi.org/10.1111/bcp.14156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983506PMC
January 2020

The Oral Pheneticillin Absorption Test: An Accurate Method to Identify Patients with Inadequate Oral Pheneticillin Absorption.

Antibiotics (Basel) 2019 Aug 15;8(3). Epub 2019 Aug 15.

Centre for Human Drug Research (CHDR), 2333 CL Leiden, The Netherlands.

Severe streptococcal infections are commonly treated with intravenous followed by oral penicillin (pheneticillin) therapy. However, switching from iv to oral therapy is complicated by the variability in oral pheneticillin absorption. We employed an Oral Absorption Test (OAT) for pheneticillin to identify patients in whom oral pheneticillin absorption is poor. Out of 84 patients 30 patients (36%) were identified as insufficient absorbers. Treatment failure due to pheneticillin malabsorption can be avoided by performing an OAT, and these patients should be treated by another antibiotic, which is known to be absorbed well.
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http://dx.doi.org/10.3390/antibiotics8030119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784104PMC
August 2019

A zwitterionic near-infrared fluorophore for real-time ureter identification during laparoscopic abdominopelvic surgery.

Nat Commun 2019 07 16;10(1):3118. Epub 2019 Jul 16.

Leiden University Medical Center, Leiden, The Netherlands.

Iatrogenic injury of the ureters is a feared complication of abdominal surgery. Zwitterionic near-infrared fluorophores are molecules with geometrically-balanced, electrically-neutral surface charge, which leads to renal-exclusive clearance and ultralow non-specific background binding. Such molecules could solve the ureter mapping problem by providing real-time anatomic and functional imaging, even through intact peritoneum. Here we present the first-in-human experience of this chemical class, as well as the efficacy study in patients undergoing laparoscopic abdominopelvic surgery. The zwitterionic near-infrared fluorophore ZW800-1 is safe, has pharmacokinetic properties consistent with an ideal blood pool agent, and rapid elimination into urine after a single low-dose intravenous injection. Visualization of structure and function of the ureters starts within minutes after ZW800-1 injection and lasts several hours. Zwitterionic near-infrared fluorophores add value during laparoscopic abdominopelvic surgeries and could potentially decrease iatrogenic urethral injury. Moreover, ZW800-1 is engineered for one-step covalent conjugatability, creating possibilities for developing novel targeted ligands.
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http://dx.doi.org/10.1038/s41467-019-11014-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635391PMC
July 2019

A Novel Somatostatin-Dopamine Chimera (BIM23B065) Reduced GH Secretion in a First-in-Human Clinical Trial.

J Clin Endocrinol Metab 2019 03;104(3):883-891

Centre for Human Drug Research, Leiden, Netherlands.

Context: A somatostatin-dopamine chimera (BIM23B065) was under investigation to reduce GH secretion for the treatment of pituitary adenomas.

Objective: To determine pharmacokinetics, safety, and tolerability and to monitor hormonal changes after single and multiple subcutaneous BIM23B065 administrations.

Design: Randomized, double-blind, placebo-controlled, parallel-group design with five single and three 13-day multiple ascending-dose cohorts.

Patients: A total of 63 healthy male white volunteers were enrolled (47 active, 16 placebo).

Main Outcome Measures: Pharmacokinetics, GH, prolactin (PRL), IGF-1, GH after GHRH administration, and general clinical safety criteria.

Results: The maximum dosage of BIM23B065 administered in this study was 1.5 mg. BIM23B065 reduced the mean GH concentrations after 8 and 13 days of treatment. A decrease in GH release after GHRH administration indicated inhibition of the hypothalamic-pituitary-somatotropic axis. IGF-1 was not altered after single doses but showed a significant change from baseline after multiple dosing. PRL secretion was reduced in all subjects who were treated. Orthostatic hypotension and injection site reactions were commonly observed at high dosages. A 6-day uptitration period was included to successfully lower the cardiovascular effects in the multiple ascending dose part of the study.

Conclusions: Proof of pharmacology of BIM23B065 was shown by a reduction in GH, IGF-1, and PRL concentrations in healthy male volunteers, supporting activity of the somatostatin analog and dopamine agonist moieties. The safety and tolerability of the higher dosing regions was limited mainly by orthostatic hypotension.
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http://dx.doi.org/10.1210/jc.2018-01364DOI Listing
March 2019

Population Pharmacokinetic/Pharmacodynamic Analysis of Nociceptive Pain Models Following an Oral Pregabalin Dose Administration to Healthy Subjects.

CPT Pharmacometrics Syst Pharmacol 2018 09 13;7(9):573-580. Epub 2018 Aug 13.

Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

A battery of pain models can be used in clinical trials to investigate the efficacy and to establish the concentration-effect relationship of novel analgesics. This study quantified the pharmacokinetics (PK) of pregabalin after a single oral dose of 300 mg and the pharmacodynamics (PD) on the pain tolerance threshold (PTT) of the cold pressor, electrical stimulation, the pressure pain model, and on the pain detection threshold of a contact heat pain model. The PK were best described using a one-compartment model with lag time, linear absorption, and linear elimination. The PTT of the cold pressor showed a negative linear decrease over time without pregabalin. A linear drug effect was identified on the PTT of the cold pressor test and an on/off effect for the electrical stimulation PTT. No PK/PD relationship could be identified on the pressure pain and heat pain test. Citation.
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http://dx.doi.org/10.1002/psp4.12318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157667PMC
September 2018

How are growth hormone and insulin-like growth factor-1 reported as markers for drug effectiveness in clinical acromegaly research? A comprehensive methodologic review.

Pituitary 2018 Jun;21(3):310-322

Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.

Objective: In rare disease research, most randomized prospective clinical trials can only use limited number of patients and are comprised of highly heterogeneous populations. Therefore, it is crucial to report the results in such a manner that it allows for comparison of treatment effectiveness and biochemical control between studies. The aim of this review was to investigate the current methods that are being applied to measure and report growth hormone (GH) and insulin-like growth factor-1 (IGF-1) as markers for drug effectiveness in clinical acromegaly research.

Search Strategy: A systematic search of recent prospective and retrospective studies, published between 2012 and 2017, that studied the effects of somatostatin analogues or dopamine agonists in acromegaly patients was performed. The markers of interest were GH, IGF-1, and the suppression of GH after an oral glucose tolerance test (OGTT). Additionally, the use of pharmacokinetic (PK) measurements in these studies was analyzed. The sampling design, cut-off for biochemical control, reported units, and used summary statistics were summarized.

Results: A total of 49 articles were selected out of the 263 screened abstracts. IGF-1 concentrations were measured in all 49 studies, GH in 45 studies, and an OGTT was performed in 11 studies. A wide range of different cut-off values and sampling designs were used to determine biochemical control in acromegaly patients. The summary statistics were reported in various ways, with the percentage of biochemical control most frequently used. Nine studies sampled the PK at one or more time points. Non-compartmental analyses were commonly performed on the available PK data.

Conclusions: The way GH and IGF-1 are measured and reported in acromegaly research varies considerably. A consensus on how to report study results would enable better comparisons between studies, thereby improving evidence based decision making to optimize treatment in acromegaly.
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http://dx.doi.org/10.1007/s11102-018-0884-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942341PMC
June 2018

A two-step deconvolution-analysis-informed population pharmacodynamic modeling approach for drugs targeting pulsatile endogenous compounds.

J Pharmacokinet Pharmacodyn 2017 08 11;44(4):389-400. Epub 2017 May 11.

Centre for Human Drug Research, Leiden, The Netherlands.

Pharmacodynamic modeling of pulsatile endogenous compounds (e.g. growth hormone [GH]) is currently limited to the identification of a low number of pulses. Commonly used pharmacodynamic models are not able to capture the complexity of pulsatile secretion and therefore non-compartmental analyses are performed to extract summary statistics (mean, AUC, C). The aim of this study was to develop a new quantification method that deals with highly variable pulsatile data by using a deconvolution-analysis-informed population pharmacodynamic modeling approach. Pulse frequency and pulse times were obtained by deconvolution analysis of 24 h GH profiles. The estimated pulse times then informed a non-linear mixed effects population pharmacodynamic model in NONMEM V7.3. The population parameter estimates were used to perform simulations that show agonistic and antagonistic drug effects on the secretion of GH. Additionally, a clinical trial simulation shows the application of this method in the quantification of a hypothetical drug effect that inhibits GH secretion. The GH profiles were modeled using a turnover compartment in which the baseline secretion, k, pulse secretion width, amount at time point 0 and pulse amplitude were estimated as population parameters. Population parameters were estimated with low relative standard errors (ranging from 2 to 5%). Total body water (%) was identified as a covariate for pulse amplitude, baseline secretion and the pulse secretion width following a power relationship. Simulations visualized multiple gradients of a hypothetical drug that influenced the endogenous secretion of GH. The established model was able to fit and quantify the highly variable individual 24 h GH profiles over time. This pharmacodynamic model can be used to quantify drug effects that target other endogenous pulsatile compounds.
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http://dx.doi.org/10.1007/s10928-017-9526-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514197PMC
August 2017

Integration of pharmacometabolomics with pharmacokinetics and pharmacodynamics: towards personalized drug therapy.

Metabolomics 2017 19;13(1). Epub 2016 Dec 19.

Division of Analytical Biosciences, Systems Pharmacology Cluster, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.

Personalized medicine, in modern drug therapy, aims at a tailored drug treatment accounting for inter-individual variations in drug pharmacology to treat individuals effectively and safely. The inter-individual variability in drug response upon drug administration is caused by the interplay between drug pharmacology and the patients' (patho)physiological status. Individual variations in (patho)physiological status may result from genetic polymorphisms, environmental factors (including current/past treatments), demographic characteristics, and disease related factors. Identification and quantification of predictors of inter-individual variability in drug pharmacology is necessary to achieve personalized medicine. Here, we highlight the potential of pharmacometabolomics in prospectively informing on the inter-individual differences in drug pharmacology, including both pharmacokinetic (PK) and pharmacodynamic (PD) processes, and thereby guiding drug selection and drug dosing. This review focusses on the pharmacometabolomics studies that have additional value on top of the conventional covariates in predicting drug PK. Additionally, employing pharmacometabolomics to predict drug PD is highlighted, and we suggest not only considering the endogenous metabolites as static variables but to include also drug dose and temporal changes in drug concentration in these studies. Although there are many endogenous metabolite biomarkers identified to predict PK and more often to predict PD, validation of these biomarkers in terms of specificity, sensitivity, reproducibility and clinical relevance is highly important. Furthermore, the application of these identified biomarkers in routine clinical practice deserves notable attention to truly personalize drug treatment in the near future.
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http://dx.doi.org/10.1007/s11306-016-1143-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5165030PMC
December 2016