Publications by authors named "G H Groeneveld"

142 Publications

Effect of sustained high buprenorphine plasma concentrations on fentanyl-induced respiratory depression: A placebo-controlled crossover study in healthy volunteers and opioid-tolerant patients.

PLoS One 2022 27;17(1):e0256752. Epub 2022 Jan 27.

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

Background: Opioid-induced respiratory depression driven by ligand binding to mu-opioid receptors is a leading cause of opioid-related fatalities. Buprenorphine, a partial agonist, binds with high affinity to mu-opioid receptors but displays partial respiratory depression effects. The authors examined whether sustained buprenorphine plasma concentrations similar to those achieved with some extended-release injections used to treat opioid use disorder could reduce the frequency and magnitude of fentanyl-induced respiratory depression.

Methods: In this two-period crossover, single-centre study, 14 healthy volunteers (single-blind, randomized) and eight opioid-tolerant patients taking daily opioid doses ≥90 mg oral morphine equivalents (open-label) received continuous intravenous buprenorphine or placebo for 360 minutes, targeting buprenorphine plasma concentrations of 0.2 or 0.5 ng/mL in healthy volunteers and 1.0, 2.0 or 5.0 ng/mL in opioid-tolerant patients. Upon reaching target concentrations, participants received up to four escalating intravenous doses of fentanyl. The primary endpoint was change in isohypercapnic minute ventilation (VE). Additionally, occurrence of apnea was recorded.

Results: Fentanyl-induced changes in VE were smaller at higher buprenorphine plasma concentrations. In healthy volunteers, at target buprenorphine concentration of 0.5 ng/mL, the first and second fentanyl boluses reduced VE by [LSmean (95% CI)] 26% (13-40%) and 47% (37-59%) compared to 51% (38-64%) and 79% (69-89%) during placebo infusion (p = 0.001 and < .001, respectively). Discontinuations for apnea limited treatment comparisons beyond the second fentanyl injection. In opioid-tolerant patients, fentanyl reduced VE up to 49% (21-76%) during buprenorphine infusion (all concentration groups combined) versus up to 100% (68-132%) during placebo infusion (p = 0.006). In opioid-tolerant patients, the risk of experiencing apnea requiring verbal stimulation following fentanyl boluses was lower with buprenorphine than with placebo (odds ratio: 0.07; 95% CI: 0.0 to 0.3; p = 0.001).

Interpretation: Results from this proof-of-principle study provide the first clinical evidence that high sustained plasma concentrations of buprenorphine may protect against respiratory depression induced by potent opioids like fentanyl.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256752PLOS
January 2022

A Randomized Trial Assessing the Safety, Pharmacokinetics, and Efficacy During Morning Off of AZ-009.

Mov Disord 2022 Jan 20. Epub 2022 Jan 20.

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

Background: Inhalation of apomorphine could be a faster-acting and more user-friendly alternative to subcutaneous injection for treating off periods in Parkinson's disease (PD).

Objective: The aim of this study was to compare the safety and pharmacokinetics of inhaled apomorphine (AZ-009) with subcutaneous apomorphine (APO-go PEN) in healthy volunteers (HVs) and to examine the safety, pharmacokinetics, and efficacy of AZ-009 in patients with PD.

Methods: In part A of this study, eight HVs received 1 mg AZ-009 and 2 mg subcutaneous apomorphine in a randomized crossover manner. In the subsequent single ascending dose parts in HVs (part B, n = 16) and patients with PD (part C, n = 25), participants were randomized to placebo or AZ-009 up to 4 mg. In patients, after medication withdrawal, Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III and on/off states were assessed predose and postdose.

Results: AZ-009 was rapidly absorbed with peak plasma concentrations at 2 minutes, as compared to 30 minutes for subcutaneous apomorphine. Adverse events for AZ-009 were comparable to subcutaneous apomorphine, except for mild and transient throat irritation. Adverse events limited AZ-009 dose escalation in HVs to 3 mg. Patients tolerated up to 4 mg. In patients with PD, 2, 3, and 4 mg AZ-009 reduced mean Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III score (standard deviation) by 10.7 (13.6), 12.8 (7.9), and 10.3 (3.7) points, respectively, compared to 4.8 (4.9) after placebo at 10 minutes postdose. The percentage of patients achieving full on within 45 minutes postdose increased dose dependently: 0% (placebo), 17% (2 mg), 50% (3 mg), and 83% (4 mg).

Conclusions: AZ-009 appears to be a rapid-acting and reasonably well-tolerated formulation for treating off periods. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28926DOI Listing
January 2022

TRANSCRANIAL MAGNETIC STIMULATION AS BIOMARKER OF EXCITABILITY IN DRUG DEVELOPMENT: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, CROSS-OVER STUDY.

Br J Clin Pharmacol 2022 Jan 13. Epub 2022 Jan 13.

Centre for Human Drug Research, Leiden, The Netherlands.

Aim: The purpose of this study was to investigate pharmacodynamic effects of drugs targeting cortical excitability using transcranial magnetic stimulation (TMS) combined with electromyography (EMG) and electroencephalography (EEG) in healthy subjects, to further develop TMS outcomes as biomarkers for proof-of-mechanism in early phase clinical drug development. Anti-epileptic drugs presumably modulate cortical excitability. Therefore, we studied effects of levetiracetam, valproic acid and lorazepam on cortical excitability in a double-blind, placebo-controlled, four-way cross-over study.

Methods: In 16 healthy male subjects, single- and paired-pulse TMS-EMG-EEG measurements were performed pre-dose and 1.5, 7, and 24 hours post-dose. Treatment effects on motor-evoked potential (MEP), short (SICI) and long intra-cortical inhibition (LICI) and TMS-evoked potential (TEP) amplitudes, were analysed using a mixed model ANCOVA and cluster-based permutation analysis.

Results: We show that MEP amplitudes decreased after administration of levetiracetam (estimated difference (ED) -378.4μV; 95%CI: -644.3μV, -112.5μV; p<0.01), valproic acid (ED -268.8μV; 95%CI: -532.9μV, -4.6μV; p=0.047) and lorazepam (ED -330.7μV; 95%CI: -595.6μV, -65.8μV; p=0.02) when compared with placebo. LICI was enhanced by levetiracetam (ED -60.3%; 95%CI: -87.1%, -33.5%; p<0.001) and lorazepam (ED -68.2%; 95%CI: -94.7%, -41.7%; p<0.001) at a 50 ms interstimulus interval. Levetiracetam increased TEP-component N45 (p=0.004) in a central cluster and decreased N100 (p<0.001) in a contralateral cluster.

Conclusions: In conclusion, this study shows that levetiracetam, valproic acid and lorazepam decrease cortical excitability, which can be detected using TMS-EMG-EEG in healthy subjects. These findings provide support for the use of TMS excitability measures as biomarkers to demonstrate pharmacodynamic effects of drugs that influence cortical excitability.
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http://dx.doi.org/10.1111/bcp.15232DOI Listing
January 2022

Simultaneous measurement of intra-epidermal electric detection thresholds and evoked potentials for observation of nociceptive processing following sleep deprivation.

Exp Brain Res 2022 Jan 7. Epub 2022 Jan 7.

Biomedical Signals and Systems, Technical Medical Centre, University of Twente, Drienerlolaan 5, PO Box 217, 7500 AE, Enschede, The Netherlands.

Sleep deprivation has been shown to increase pain intensity and decrease pain thresholds in healthy subjects. In chronic pain patients, sleep impairment often worsens the perceived pain intensity. This increased pain perception is the result of altered nociceptive processing. We recently developed a method to quantify and monitor altered nociceptive processing by simultaneous tracking of psychophysical detection thresholds and recording of evoked cortical potentials during intra-epidermal electric stimulation. In this study, we assessed the sensitivity of nociceptive detection thresholds and evoked potentials to altered nociceptive processing after sleep deprivation in an exploratory study with 24 healthy male and 24 healthy female subjects. In each subject, we tracked nociceptive detection thresholds and recorded central evoked potentials in response to 180 single- and 180 double-pulse intra-epidermal electric stimuli. Results showed that the detection thresholds for single- and double-pulse stimuli and the average central evoked potential for single-pulse stimuli were significantly decreased after sleep deprivation. When analyzed separated by sex, these effects were only significant in the male population. Multivariate analysis showed that the decrease of central evoked potential was associated with a decrease of task-related evoked activity. Measurement repetition led to a decrease of the detection threshold to double-pulse stimuli in the mixed and the female population, but did not significantly affect any other outcome measures. These results suggest that simultaneous tracking of psychophysical detection thresholds and evoked potentials is a useful method to observe altered nociceptive processing after sleep deprivation, but is also sensitive to sex differences and measurement repetition.
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http://dx.doi.org/10.1007/s00221-021-06284-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8739349PMC
January 2022

Detection of Clenbuterol-Induced Changes in Heart Rate Using At-Home Recorded Smartwatch Data: Randomized Controlled Trial.

JMIR Form Res 2021 Dec 30;5(12):e31890. Epub 2021 Dec 30.

Centre for Human Drug Research, Leiden, Netherlands.

Background: Although electrocardiography is the gold standard for heart rate (HR) recording in clinical trials, the increasing availability of smartwatch-based HR monitors opens up possibilities for drug development studies. Smartwatches allow for inexpensive, unobtrusive, and continuous HR estimation for potential detection of treatment effects outside the clinic, during daily life.

Objective: The aim of this study is to evaluate the repeatability and sensitivity of smartwatch-based HR estimates collected during a randomized clinical trial.

Methods: The data were collected as part of a multiple-dose, investigator-blinded, randomized, placebo-controlled, parallel-group study of 12 patients with Parkinson disease. After a 6-day baseline period, 4 and 8 patients were treated for 7 days with an ascending dose of placebo and clenbuterol, respectively. Throughout the study, the smartwatch provided HR and sleep state estimates. The HR estimates were quantified as the 2.5th, 50th, and 97.5th percentiles within awake and asleep segments. Linear mixed models were used to calculate the following: (1) the intraclass correlation coefficient (ICC) of estimated sleep durations, (2) the ICC and minimum detectable effect (MDE) of the HR estimates, and (3) the effect sizes of the HR estimates.

Results: Sleep duration was moderately repeatable (ICC=0.64) and was not significantly affected by study day (P=.83), clenbuterol (P=.43), and study day by clenbuterol (P=.73). Clenbuterol-induced changes were detected in the asleep HR as of the first night (+3.79 beats per minute [bpm], P=.04) and in the awake HR as of the third day (+8.79 bpm, P=.001). The median HR while asleep had the highest repeatability (ICC=0.70). The MDE (N=12) was found to be smaller when patients were asleep (6.8 bpm to 11.7 bpm) than while awake (10.7 bpm to 22.1 bpm). Overall, the effect sizes for clenbuterol-induced changes were higher while asleep (0.49 to 2.75) than while awake (0.08 to 1.94).

Conclusions: We demonstrated the feasibility of using smartwatch-based HR estimates to detect clenbuterol-induced changes during clinical trials. The asleep HR estimates were most repeatable and sensitive to treatment effects. We conclude that smartwatch-based HR estimates obtained during daily living in a clinical trial can be used to detect and track treatment effects.

Trial Registration: Netherlands Trials Register NL8002; https://www.trialregister.nl/trial/8002.
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http://dx.doi.org/10.2196/31890DOI Listing
December 2021
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