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Martini C.,Leiden University | Olofsen E.,Leiden University | Yassen A.,Global Clinical Pharmacology and Exploratory Development | Aarts L.,Leiden University | Dahan A.,Leiden University
Expert Review of Clinical Pharmacology | Year: 2011

In acute and chronic pain, the objective of pharmacokinetic-pharmacodynamic (PKPD) modeling is the development and application of mathematical models to describe and/or predict the time course of the pharmacokinetics (PK) and pharmacodynamics (PD) of analgesic agents and link PK to PD. Performing population PKPD modeling using nonlinear mixed effects modeling allows, apart from the estimation of fixed effects (the PK and PD model estimates), the quantification of random effects as within- and between-subject variability. Effect-compartment models and mechanism-based biophase distribution models that incorporate drug-association and -dissociation kinetics are applied in PKPD modeling of pain treatment. Mechanism-based models enable the quantification of the rate-limiting factors in drug effect owing to drug distribution versus receptor kinetics (since receptor kinetics are nonlinear they are discernable from the linear effect-compartment kinetics). It is a helpful technique in understanding the complex behavior of specific analgesics, such as buprenorphine, but also morphine and its active metabolite morphine-6- glucuronide, especially with respect to the reversal of opioid-induced side effects, most importantly life-threatening respiratory depression. One approach in chronic pain studies is the application of mixture models. Mixture models do not necessarily need to take PK data into account and allow the objective differentiation of measured responses to analgesics into specific response subgroups, and as such, may play an important role in analyzing Phase I and II analgesia studies. Appropriate application of PKPD modeling leads to the improvement of current therapeutics with respect to dose design and outcome, understanding the interaction of analgesics within complex chronic pain disease processes and may play an important role in drug development. In the current article, novel observations using the aforementioned techniques on opioids, NSAIDs, epidural analgesia, ketamine and GABA-ergic drugs in acute and chronic pain are discussed. © 2011 Albert Dahan.

Martini C.H.,Leiden University | Yassen A.,Global Clinical Pharmacology and Exploratory Development | Krebs-Brown A.,Global Data science | Passier P.,Global Clinical Pharmacology and Exploratory Development | And 3 more authors.
European Journal of Pain (United Kingdom) | Year: 2013

Background: Treatment of chronic pain conditions is commonly assessed at specific endpoints at preset times during or after treatment by analysis of the total study population. An alternative approach is the identification of specific patient subgroups characterized by differential response patterns in their analgesic response and to determine the presence of significant predictors of effect. Methods: Data from four double-blind, randomized controlled trials on the efficacy of topical capsaicin 8% (Qutenza) versus an active control (capsaicin 0.04%) in patients with postherpetic neuropathic pain were combined. Longitudinal pharmacodynamic, mixture and covariate analyses were performed on the pooled dataset. Results: Data from 1248 patients treated with Qutenza (n = 722) or topical low-dose capsaicin 0.04% (n = 526) were successfully analysed. Five distinct response subgroups were detected with different treatment efficacies, including a group of non-responders, a group showing partial analgesic effect and a group showing full analgesic effect. Active control and Qutenza had similar response profiles, but the proportional distribution of patients among the five response groups was in favour of Qutenza, with 40% less non-responders and 25% more patients showing a full analgesic response. For Qutenza, important predictors of efficacy were efficacy of lidocaine pretreatment and greater pretreatment pain score variability. Conclusions: The analyses indicate the existence of different response groups to treatment with Qutenza and an active control patch that may possibly be related to different pain mechanisms among these groups, despite a presumed common underlying disease process, and that require different treatment approaches among subgroups. © 2013 European Federation of International Association for the Study of Pain Chapters.

Martini C.,Leiden University | Yassen A.,Global Clinical Pharmacology and Exploratory Development | Olofsen E.,Leiden University | Passier P.,Global Clinical Pharmacology and Exploratory Development | And 2 more authors.
Journal of Pain Research | Year: 2012

Treatment of chronic pain is associated with high variability in the response to pharmacological interventions. A mathematical pharmacodynamic model was developed to quantify the magnitude and onset/offset times of effect of a single capsaicin 8% patch application in the treatment of painful diabetic peripheral neuropathy in 91 patients. In addition, a mixture model was applied to objectively match patterns in pain-associated behavior. The model identified four distinct subgroups that responded differently to treatment: 3.3% of patients (subgroup 1) showed worsening of pain; 31% (subgroup 2) showed no change; 32% (subgroup 3) showed a quick reduction in pain that reached a nadir in week 3, followed by a slow return towards baseline (16% ± 6% pain reduction in week 12); 34% (subgroup 4) showed a quick reduction in pain that persisted (70% ± 5% reduction in week 12). The estimate of the response-onset rate constant, obtained for subgroups 1, 3, and 4, was 0.76 ± 0.12 week-1 (median ± SE), indicating that every 0.91 weeks the pain score reduces or increases by 50% relative to the score of the previous week (= t1/2). The response-offset rate constant could be determined for subgroup 3 only and was 0.09 ± 0.04 week-1 (t1/2 7.8 weeks). The analysis allowed separation of a heterogeneous neuropathic pain population into four homogenous subgroups with distinct behaviors in response to treatment with capsaicin. It is argued that this model-based approach may have added value in analyzing longitudinal chronic pain data and allows optimization of treatment algorithms for patients suffering from chronic pain conditions. © 2012 Martini et al, publisher and licensee Dove Medical Press Ltd.

Strougo A.,Leiden University | Yassen A.,Global Clinical Pharmacology and Exploratory Development | Monnereau C.,Leiden University | Danhof M.,Leiden University | Freijer J.,Global Clinical Pharmacology and Exploratory Development
Journal of Clinical Pharmacology | Year: 2014

First-dose-in-children relies on the prediction of clearance from adults for which little information is available on the accuracy of the scaling-approaches applied. For CYP3A-metabolized compounds, scaling of clearance is further challenged by different isoforms and by the CYP3A7 to CYP3A4 switch at young ages. This investigation aimed to evaluate the accuracy of two frequently used scaling approaches and to gain insights into the ontogeny of CYP3A. Hence, a literature database was compiled containing 203 clearance values from term-neonates to adults for 18 CYP3A-metabolized compounds. The clearances in adults were scaled to children using (i) allometric scaling plus maturation function and (ii) a mechanistic approach based on the well-stirred model. Three maturation functions were separately evaluated. In children >3 months, all approaches were interchangeable heeding the maturation function applied and biases were mostly observed in children <3 months. The results from a sensitivity analysis indicate that these biases are possibly caused by disregarding the CYP3A7 activity which could account for up to 86% of the metabolism in term-neonates. Only the mechanistic approach using an overall-CYP3A maturation function led to unbiased predictions of clearances across all ages. The current investigation adds to the predictions of the first-dose-in-children of compounds (partially) metabolized by CYP3A. © 2014, The American College of Clinical Pharmacology.

Malik M.,Imperial College London | Hnatkova K.,St. Pauls Cardiac Electrophysiology | Kowalski D.,Global Clinical Pharmacology and Exploratory Development | Keirns J.J.,Global Clinical Pharmacology and Exploratory Development | van Gelderen E.M.,Global Clinical Pharmacology and Exploratory Development
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2013

Data of a large clinical study were used to investigate how much are the QT/RR patterns in healthy subjects curved and whether these curvatures differ between women and men. Daytime drug-free 12-lead Holter recordings were repeated 4 times in each of 176 female healthy subjects and 176 male healthy subjects aged 32.7 ± 9.1 yr. In each of the subjects, up to 1,440 carefully verified QT interval measurements were obtained with QT/RR hysteresis-corrected RR intervals. Individual subject data were used to fit the following regression equation: QT = χ + (δ/γ)(1- RRγ) + ε, where QT and RR are QT and RR measurements (in s), δ is regression intercept, γ is the QT/RR slope, δ is the QT/RR curvature and provides the lowest regression residual, and ε represents normally distributed zero-centered errors. The bootstrap technique showed the intrasubject reproducibility of QT/RR slopes and curvatures. In women and men, QT/RR curvatures were 0.544 ± 0.661 and 0.797 ± 0.706, respectively (P = 0.0006). The corresponding QT/RR slopes were 0.158 ± 0.030 and 0.139 ± 0.023, respectively (P < 0.0001). QT/RR curvatures were related to QT/RR slopes but not to individually corrected mean QTc intervals or individual QT/RR hysteresis profiles. The individual heart rate correction formula derived from the curvilinear regression provided a significantly lower intrasubject variability of QTc interval than individual optimisation of linear or log-linear QT/RR heart rate corrections. The QT/RR curvature can be reliable measured and expressed numerically. The corresponding heart rate correction formula provides more compact data than the previously proposed approaches. There are substantial sex differences in QT/RR patterns. Women have a QT/RR pattern that is not only steeper than men but also more curved. © 2013 the American Physiological Society.

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