| 1. |
- Juul, Rasmus Vestergaard, et al.
(författare)
-
A Pharmacokinetic-Pharmacodynamic Model of Morphine Exposure and Subsequent Morphine Consumption in Postoperative Pain
- 2016
-
Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 33:5, s. 1093-1103
-
Tidskriftsartikel (refereegranskat)abstract
- To characterize the pharmacokinetic-pharmacodynamic (PK-PD) relationship between exposure of morphine and subsequent morphine consumption and to develop simulation tools for model validation. Dose, formulation and time of morphine administration was available from a published study in 63 patients receiving intravenous, oral immediate release or oral controlled release morphine on request after hip surgery. The PK-PD relationship between predicted exposure of morphine and morphine consumption was modeled using repeated time to event (RTTE) modeling in NONMEM. To validate the RTTE model, a visual predictive check method was developed with simulated morphine consumption given the exposure of preceding morphine administration. The probability of requesting morphine was found to be significantly related to the exposure of morphine as well as night/day. Oral controlled release morphine was more effective than intravenous and oral immediate release formulations at equivalent average concentrations. Maximum effect was obtained for 8 h by oral controlled release doses a parts per thousand yenaEuro parts per thousand 15 mg, where probability of requesting a new dose was reduced to 20% for a typical patient. This study demonstrates the first quantitative link between exposure of morphine and subsequent morphine consumption and introduces an efficient visual predictive check approach with simulation of adaptive dosing.
|
|
| 2. |
- Juul, Rasmus Vestergaard, et al.
(författare)
-
Analysis of opioid consumption in clinical trials : a simulation based analysis of power of four approaches
- 2017
-
Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : SPRINGER/PLENUM PUBLISHERS. - 1567-567X .- 1573-8744. ; 44:4, s. 325-333
-
Tidskriftsartikel (refereegranskat)abstract
- Inconsistent trial design and analysis is a key reason that few advances in postoperative pain management have been made from clinical trials analyzing opioid consumption data. This study aimed to compare four different approaches to analyze opioid consumption data. A repeated time-to-event (RTTE) model in NONMEM was used to simulate clinical trials of morphine consumption with and without a hypothetical adjuvant analgesic in doses equivalent to 15-62% reduction in morphine consumption. Trials were simulated with duration of 24-96 h. Monte Carlo simulation and re-estimation were performed to determine sample size required to demonstrate efficacy with 80% power using t test, Mann-Whitney rank sum test, time-to-event (TTE) modeling and RTTE modeling. Precision of efficacy estimates for RTTE models were evaluated in 500 simulations. A sample size of 50 patients was required to detect 37% morphine sparing effect with at least 80% power in a 24 h trial with RTTE modeling whereas the required sample size was 200 for Mann-Whitney, 180 for t-test and 76 for TTE models. Extending the trial duration from 24 to 96 h reduced the required sample size by 3.1 fold with RTTE modeling. Precise estimate of potency was obtained with a RTTE model accounting for both morphine effects and time-varying covariates on opioid consumption. An RTTE analysis approach proved better suited for demonstrating efficacy of opioid sparing analgesics than traditional statistical tests as a lower sample size was required due the ability to account for time-varying factors including PK.
|
|
| 3. |
- Juul, Rasmus Vestergaard, et al.
(författare)
-
Repeated Time-to-event Analysis of Consecutive Analgesic Events in Postoperative Pain
- 2015
-
Ingår i: Anesthesiology. - 0003-3022 .- 1528-1175. ; 123:6, s. 1411-1419
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Reduction in consumption of opioid rescue medication is often used as an endpoint when investigating analgesic efficacy of drugs by adjunct treatment, but appropriate methods are needed to analyze analgesic consumption in time. Repeated time-to-event (RTTE) modeling is proposed as a way to describe analgesic consumption by analyzing the timing of consecutive analgesic events. Methods: Retrospective data were obtained from 63 patients receiving standard analgesic treatment including morphine on request after surgery following hip fracture. Times of analgesic events up to 96 h after surgery were extracted from hospital medical records. Parametric RTTE analysis was performed with exponential, Weibull, or Gompertz distribution of analgesic events using NONMEM (R), version 7.2 (ICON Development Solutions, USA). The potential influences of night versus day, sex, and age were investigated on the probability. Results: A Gompertz distribution RTTE model described the data well. The probability of having one or more analgesic events within 24 h was 80% for the first event, 55% for the second event, 31% for the third event, and 18% for fourth or more events for a typical woman of age 80 yr. The probability of analgesic events decreased in time, was reduced to 50% after 3.3 days after surgery, and was significantly lower (32%) during night compared with day. Conclusions: RTTE modeling described analgesic consumption data well and could account for time-dependent changes in probability of analgesic events. Thus, RTTE modeling of analgesic events is proposed as a valuable tool when investigating new approaches to pain management such as opioid-sparing analgesia.
|
|
| 4. |
- Lyauk, Yassine Kamal, et al.
(författare)
-
Bounded Integer Modeling of Symptom Scales Specific to Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia
- 2021
-
Ingår i: AAPS Journal. - : Springer. - 1550-7416. ; 23:2
-
Tidskriftsartikel (refereegranskat)abstract
- The International Prostate Symptom Score (IPSS), the quality of life (QoL) score, and the benign prostatic hyperplasia impact index (BII) are three different scales commonly used to assess the severity of lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH-LUTS). Based on a phase II clinical trial including 403 patients with moderate to severe BPH-LUTS, the objectives of this study were to (i) develop traditional pharmacometric and bounded integer (BI) models for the IPSS, QoL score, and BII endpoints, respectively; (ii) compare the power and type I error in detecting drug effects of BI modeling with traditional methods through simulation; and (iii) obtain quantitative translation between scores on the three abovementioned scales using a BI modeling framework. All developed models described the data adequately. Pharmacometric modeling using a continuous variable (CV) approach was overall found to be the most robust in terms of type I error and power to detect a drug effect. In most cases, BI modeling showed similar performance to the CV approach, yet severely inflated type I error was generally observed when inter-individual variability (IIV) was incorporated in the BI variance function (g()). BI modeling without IIV in g() showed greater type I error control compared to the ordered categorical approach. Lastly, a multiple-scale BI model was developed and estimated the relationship between scores on the three BPH-LUTS scales with overall low uncertainty. The current study yields greater understanding of the operating characteristics of the novel BI modeling approach and highlights areas potentially requiring further improvement.
|
|
| 5. |
- Lyauk, Yassine Kamal, et al.
(författare)
-
Integrated Item Response Theory Modeling of Multiple Patient-Reported Outcomes Assessing Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia
- 2020
-
Ingår i: AAPS Journal. - : SPRINGER. - 1550-7416. ; 22:5
-
Tidskriftsartikel (refereegranskat)abstract
- In clinical trials within lower urinary tract symptoms due to benign prostatic hyperplasia (BPH-LUTS), the International Prostate Symptom Score (IPSS) is commonly the primary efficacy outcome while the Quality of Life (QoL) score and the BPH Impact Index (BII) are common secondary efficacy markers. The current study aimed to characterize BPH-LUTS progression using responses to the IPSS, the QoL, and the BII in an integrated item response theory (IRT) framework and assess the Fisher information of each scale. The power of this approach to detect a drug effect was compared with an IRT approach considering only IPSS responses. A unidimensional and a bidimensional pharmacometric IRT model, based on item-level IPSS responses in a clinical trial with 403 patients, were extended by incorporating patients' QoL and summary BII scores over the 6-month trial period. In the developed unidimensional integrated model, the QoL score was found to be the most informative, representing 17% of the total Fisher information, while the combined information content of the seven IPSS items represented 70.6%. In the bidimensional model, "storage" and both storage and "voiding" disability drove QoL and summary BII responses, respectively. Sample size reduction of 16% to detect a drug effect at 80% power was obtained with the unidimensional integrated IRT model compared with its counterpart IPSS IRT model. This study shows that utilizing the information content across the IPSS, QoL, and BII scales in an integrated IRT framework results in a modest but meaningful increase in power to detect a drug effect.
|
|
| 6. |
- Lyauk, Yassine Kamal, et al.
(författare)
-
Item Response Theory Modeling of the International Prostate Symptom Score in Patients with Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia
- 2020
-
Ingår i: AAPS Journal. - : SPRINGER. - 1550-7416. ; 22:5
-
Tidskriftsartikel (refereegranskat)abstract
- Item response theory (IRT) was used to characterize the time course of lower urinary tract symptoms due to benign prostatic hyperplasia (BPH-LUTS) measured by item-level International Prostate Symptom Scores (IPSS). The Fisher information content of IPSS items was determined and the power to detect a drug effect using the IRT approach was examined. Data from 403 patients with moderate-to-severe BPH-LUTS in a placebo-controlled phase II trial studying the effect of degarelix over 6 months were used for modeling. Three pharmacometric models were developed: a model for total IPSS, a unidimensional IRT model, and a bidimensional IRT model, the latter separating voiding and storage items. The population-level time course of BPH-LUTS in all models was described by initial improvement followed by worsening. In the unidimensional IRT model, the combined information content of IPSS voiding items represented 72% of the total information content, indicating that the voiding subscore may be more sensitive to changes in BPH-LUTS compared with the storage subscore. The pharmacometric models showed considerably higher power to detect a drug effect compared with a cross-sectional and while-on-treatment analysis of covariance, respectively. Compared with the sample size required to detect a drug effect at 80% power with the total IPSS model, a reduction of 5.9% and 11.7% was obtained with the unidimensional and bidimensional IPSS IRT model, respectively. Pharmacometric IRT analysis of the IPSS within BPH-LUTS may increase the precision and efficiency of treatment effect assessment, albeit to a more limited extent compared with applications in other therapeutic areas.
|
|
| 7. |
- Papathanasiou, Theodoros, et al.
(författare)
-
Feasibility of Exposure-Response Analyses for Clinical Dose-Ranging Studies of Drug Combinations
- 2018
-
Ingår i: AAPS Journal. - : SPRINGER. - 1550-7416. ; 20:3
-
Tidskriftsartikel (refereegranskat)abstract
- The exposure-response relationship of combinatory drug effects can be quantitatively described using pharmacodynamic interaction models, which can be used for the selection of optimal dose combinations. The aim of this simulation study was to evaluate the reliability of parameter estimates and the probability for accurate dose identification for various underlying exposure-response profiles, under a number of different phase II designs. An efficacy variable driven by the combined exposure of two theoretical compounds was simulated and model parameters were estimated using two different models, one estimating all parameters and one assuming that adequate previous knowledge for one drug is readily available. Estimation of all pharmacodynamic parameters under a realistic, in terms of sample size and study design, phase II trial, proved to be challenging. Inaccurate estimates were found in all exposure-response scenarios, except for situations where no pharmacodynamic interaction was present, with the drug potency and interaction parameters being the hardest to estimate. When previous knowledge of the exposure-response relationship of one of the monocomponents is available, such information should be utilized, as it enabled relevant improvements in parameter estimation and in correct dose identification. No general trends for classification of the performance of the tested study designs across different scenarios could be identified. This study shows that pharmacodynamic interactions models can be used for the exposure-response analysis of clinical endpoints especially when accompanied by appropriate dose selection in regard to the expected drug potencies and appropriate trial size and if information regarding the exposure-response profile of one monocomponent is available.
|
|
| 8. |
- Papathanasiou, Theodoros, et al.
(författare)
-
High-dose naloxone, an experimental tool uncovering latent sensitisation : pharmacokinetics in humans
- 2019
-
Ingår i: British Journal of Anaesthesia. - : Elsevier BV. - 0007-0912. ; 123:2, s. 204-214
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Naloxone, an opioid receptor antagonist, is used as a pharmacological tool to detect tonic endogenous activation of opioid receptors in experimental pain models. We describe a pharmacokinetic model linking naloxone pharmacokinetics to its main metabolite after high-dose naloxone infusion. Methods: Eight healthy volunteers received a three-stage stepwise high-dose i.v. naloxone infusion (total dose 3.25 mg kg−1). Naloxone and naloxone-3-glucuronide (N3G) plasma concentrations were sampled from infusion onset to 334 min after infusion discontinuation. Pharmacokinetic analysis was performed using non-linear mixed effect models (NONMEM). The predictive performances of Dowling's and Yassen's models were evaluated, and target-controlled infusion simulations were performed. Results: Three- and two-compartment disposition models with linear elimination kinetics described the naloxone and N3G concentration time-courses, respectively. Two covariate models were developed: simple (weight proportional) and complex (with the shallow peripheral volume of distribution linearly increasing with body weight). The median prediction error (MDPE) and wobble for Dowling's model were –32.5% and 33.4%, respectively. For Yassen's model, the MDPE and wobble were 1.2% and 19.9%, respectively. Conclusions: A parent–metabolite pharmacokinetic model was developed for naloxone and N3G after high-dose naloxone infusion. No saturable pharmacokinetics were observed. Whereas Dowling's model was inaccurate and over-predicted naloxone concentrations, Yassen's model accurately predicted naloxone pharmacokinetics. The newly developed covariate models may be used for high-dose TCI-naloxone for experimental and clinical practice. Clinical trials registration: NCT01992146.
|
|
| 9. |
- Papathanasiou, Theodoros, et al.
(författare)
-
Optimizing Dose-Finding Studies for Drug Combinations Based on Exposure-Response Models
- 2019
-
Ingår i: AAPS Journal. - : SPRINGER. - 1550-7416. ; 21:5
-
Tidskriftsartikel (refereegranskat)abstract
- Combinations of pharmacological treatments are increasingly being investigated for potentially higher clinical benefit, especially when the combined drugs are expected to act via synergistic interactions. The clinical development of combination treatments is particularly challenging, particularly during the dose-selection phase, where a vast range of possible combination doses exists. The purpose of this work was to evaluate the added value of using optimal design for guiding the dose allocation in drug combination dose-finding studies as compared with a typical drug-combination trial. Optimizations were performed using local [D(s)-optimality] and global [ED(s)-optimality] optimal designs to maximize the precision of model parameters in a number of potential exposure-response (E-R) surfaces. A compound criterion [D(s)/V-optimality] was used to optimize the precision of model predictions in specific parts of the E-R surfaces. Optimal designs provided unbiased estimates and significantly improved the accuracy of results relative to the typical design. It was possible to improve the efficiency and overall parameter precision up to 7832% and 96.6% respectively. When the compound criterion was used, the probability to accurately identify the optimal dose-combination increased from 71% for the typical design up to 91%. These results indicate that optimal design methodology in tandem with E-R analyses is a beneficial tool that can be used for appropriate dose allocation in dose-finding studies for drug combinations.
|
|
| 10. |
- Springborg, Anders Deichmann, et al.
(författare)
-
High-dose naloxone : Effects by late administration on pain and hyperalgesia following a human heat injury model. A randomized, double-blind, placebo-controlled, crossover trial with an enriched enrollment design
- 2020
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:11
-
Tidskriftsartikel (refereegranskat)abstract
- Severe chronic postsurgical pain has a prevalence of 4–10% in the surgical population. The underlying nociceptive mechanisms have not been well characterized. Following the late resolution phase of an inflammatory injury, high-dose μ-opioid-receptor inverse agonists reinstate hypersensitivity to nociceptive stimuli. This unmasking of latent pain sensitization has been a consistent finding in rodents while only observed in a limited number of human volunteers. Latent sensitization could be a potential triggering venue in chronic postsurgical pain. The objective of the present trial was in detail to examine the association between injury-induced secondary hyperalgesia and naloxone-induced unmasking of latent sensitization. Healthy volunteers (n = 80) received a cutaneous heat injury (47 C, 420 s, 12.5 cm2). Baseline secondary hyperalgesia areas were assessed 1 h post-injury. Utilizing an enriched enrollment design, subjects with a magnitude of secondary hyperalgesia areas in the upper quartile (‘high-sensitizers’ [n = 20]) and the lower quartile (‘low-sensitizers’ [n = 20]) were selected for further study. In four consecutive experimental sessions (Sessions 1 to 4), the subjects at two sessions (Sessions 1 and 3) received a cutaneous heat injury followed 168 h later (Sessions 2 and 4) by a three-step target-controlled intravenous infusion of naloxone (3.25 mg/kg), or normal saline. Assessments of secondary hyperalgesia areas were made immediately before and stepwise during the infusions. Simple univariate statistics revealed no significant differences in secondary hyperalgesia areas between naloxone and placebo treatments (P = 0.215), or between ‘high-sensitizers’ and ‘low-sensitizers’ (P = 0.757). In a mixed-effects model, secondary hyperalgesia areas were significantly larger following naloxone as compared to placebo for ‘high-sensitizers’ (P < 0.001), but not ‘low-sensitizers’ (P = 0.651). Although we could not unequivocally demonstrate naloxone-induced reinstatement of heat injury-induced hyperalgesia, further studies in clinical postsurgical pain models are warranted.
|
|
| 11. |
- Storgaard, Ida Klitzing, et al.
(författare)
-
Population pharmacokinetic–pharmacodynamic model of subcutaneous bupivacaine in a novel extended-release microparticle formulation
-
Ingår i: Basic and Clinical Pharmacology and Toxicology. - 1742-7835.
-
Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to develop a population pharmacokinetic–pharmacodynamic model of subcutaneously administered bupivacaine in a novel extended-release microparticle formulation for postoperative pain management. Bupivacaine was administered subcutaneously in the lower leg to 28 healthy male subjects in doses from 150 to 600 mg in a phase 1 randomized, placebo-controlled, double-blind, dose-ascending study with two different microparticle formulations, LIQ865A and LIQ865B. Warmth detection threshold was used as a surrogate pharmacodynamic endpoint. Population pharmacokinetic–pharmacodynamic models were fitted to plasma concentration-effect-time data using non-linear mixed-effects modelling. The pharmacokinetics were best described by a two-compartment model with biphasic absorption as two parallel absorption processes: a fast, zero-order process and a slower, first-order process with two transit compartments. The slow absorption process was found to be dose-dependent and rate-limiting for elimination at higher doses. Apparent bupivacaine clearance and the transit rate constant describing the slow absorption process both appeared to decrease with increasing doses following a power function with a shared covariate effect. The pharmacokinetic–pharmacodynamic relationship between plasma concentrations and effect was best described by a linear function. This model gives new insight into the pharmacokinetics and pharmacodynamics of microparticle formulations of bupivacaine and the biphasic absorption seen for several local anaesthetics.
|
|
