| 1. |
- Brokjaer, Anne, et al.
(författare)
-
Population pharmacokinetics of morphine and morphine-6-glucuronide following rectal administration - A dose escalation study
- 2015
-
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 68, s. 78-86
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: To safely and effectively administer morphine as liquid formulation via the rectal route, a thorough understanding of the pharmacokinetics is warranted. The aims were: (1) to develop a population pharmacokinetic model of liquid rectal morphine and morphine-6-glucoronide (M6G), (2) to simulate clinically relevant rectal doses of morphine and (3) to assess the tolerability and safety. Material and methods: This open label, dose escalation, four-sequence study was conducted in 10 healthy males. Three escalating doses of morphine hydrochloride (10 mg, 15 mg and 20 mg) were administered 20 cm from the anal verge. A 2 mg morphine hydrochloride dose was administered intravenously as reference. Blood samples were drawn at baseline and at nine time points post dosing. Serum was obtained by centrifugation and assayed for contents of morphine and M6G with a validated high performance liquid chromatographic method. Modelling was performed using NONMEM 7.2 and the first order conditional estimation method with interaction. Results: A two compartment distribution model with one absorption transit compartment for rectal administration and systemic clearance from the central compartment best described data. Systemic PK parameters were allometric scaled with body weight. The mean morphine absorption transit time was 0.6 h, clearance 78 L/h [relative standard error (RSE) 12%1 and absolute bioavailability 24% (RSE 11%). To obtain clinically relevant serum concentrations, simulations revealed that a single morphine hydrochloride dose of 35 mg will provide sufficient peak serum concentration levels and a 46 mg dose four times daily is suggested to maintain clinically relevant steady-state concentrations. Body weight was suggested to be an important covariate for morphine exposure. No severe side effects were observed. Conclusion: A population pharmacokinetic model of liquid rectal morphine and M6G was developed. The model can be used to simulate rectal doses to maintain analgesic activity in the clinic. The studied doses were safe and well tolerated. (C) 2014 Elsevier B.V. All rights reserved.
|
|
| 2. |
- 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.
|
|
| 3. |
- 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.
|
|
| 4. |
- 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.
|
|
