Pharmacokinetic/Pharmacodynamic Modelling of Venlafaxine

Lindauer, Andreas; Siepmann, Timo; Oertel, Reinhard; Jung, Angelika; Ziemssen, Tjalf; Jaehde, Ulrich; Kirch, Wilhelm; Siepmann, Martin

doi:10.2165/00003088-200847110-00003

Cited by 15 publications

(19 citation statements)

References 24 publications

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“…This might be related to the fact that venlafaxine was applied in sub-antidepressive doses, where the threshold for noradrenergic adverse effects might not have been reached. However, in an experimental setting, venlafaxine led to complex disturbances of the autonomic nervous system in a dose-dependent fashion even in the lower doses, possibly indicating a continuous dose-dependent rather than a threshold-based all or nothing mechanism of noradrenergic adverse effects (47, 48). Cognitive functions were not altered in the same expiremental setting, consistent with a predominant effect on centers of autonomic sympathetic control and efferent adrenergic pathways (49).…”

Section: Discussionmentioning

confidence: 99%

Adverse Effects of Antidepressants for Chronic Pain: A Systematic Review and Meta-analysis

et al. 2017

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BackgroundAntidepressants are widely used in the treatment of chronic pain. Applied doses are lower than those needed to unfold an antidepressive effect. While efficacy of antidepressants for chronic pain has been reported in large randomized-controlled trials (RCT), there is inconsistent data on adverse effects and tolerability. We aimed at synthesizing data from RCT to explore adverse effect profiles and tolerability of antidepressants for treatment of chronic pain.MethodsSystematic literature research and meta-analyses were performed regarding side effects and safety of different antidepressants in the treatment of chronic pain according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The National Center for Biotechnology Information library and MEDLINE were searched. Randomized placebo-controlled trials were included in quantitative data synthesis.ResultsOut of 1,975 screened articles, 33 papers published between 1995 and 2015 were included in our review and 23 studies were included in the meta-analyses. A higher risk for adverse effects compared to placebo was observed in all antidepressants included in our analyses, except nortriptyline. The most prevalent adverse effects were dry mouth, dizziness, nausea, headache, and constipation. Amitriptyline, mirtazapine, desipramine, venlafaxine, fluoxetine, and nortriptyline showed the highest placebo effect-adjusted risk of adverse effects. Risk for withdrawal due to adverse effects was highest in desipramine (risk ratio: 4.09, 95%-confidence interval [1.31; 12.82]) followed by milnacipran, venlafaxine, and duloxetine. The most common adverse effects under treatment with antidepressants were dry mouth, dizziness, nausea, headache, and constipation followed by palpitations, sweating, and drowsiness. However, overall tolerability was high. Each antidepressant showed distinct risk profiles of adverse effects.ConclusionOur synthesized data analysis confirmed overall tolerability of low-dose antidepressants for the treatment of chronic pain and revealed drug specific risk profiles. This encompassing characterization of adverse effect profiles might be useful in defining multimodal treatment regimens for chronic pain which also consider patients’ comorbidities and co-medication.

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Section: Discussionmentioning

confidence: 99%

Adverse Effects of Antidepressants for Chronic Pain: A Systematic Review and Meta-analysis

et al. 2017

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“…Pupillary reactions can be examined with computerized pupillographic devices. The most frequently measured parameters in MS patients assessing parasympathetic function are the pupillary light reflex latency (PLRL), reflex amplitude, contraction velocity, while the parameters representing sympathetic function are the redilatation velocity, time of 75% redilatation and redilatation at 5 s [ 233 , 236 , 237 , 241 ]. The PCR is also measureable by similar pupillographic equipment with the application of special stimulation with colored targets [ 238 ].…”

Section: Pupillomotor Dysfunctionmentioning

confidence: 99%

Autonomic Dysregulation in Multiple Sclerosis

Pintér

Cseh

Sárközi

et al. 2015

IJMS

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Multiple sclerosis (MS) is a chronic, progressive central neurological disease characterized by inflammation and demyelination. In patients with MS, dysregulation of the autonomic nervous system may present with various clinical symptoms including sweating abnormalities, urinary dysfunction, orthostatic dysregulation, gastrointestinal symptoms, and sexual dysfunction. These autonomic disturbances reduce the quality of life of affected patients and constitute a clinical challenge to the physician due to variability of clinical presentation and inconsistent data on diagnosis and treatment. Early diagnosis and initiation of individualized interdisciplinary and multimodal strategies is beneficial in the management of autonomic dysfunction in MS. This review summarizes the current literature on the most prevalent aspects of autonomic dysfunction in MS and provides reference to underlying pathophysiological mechanisms as well as means of diagnosis and treatment.

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“…The use of transit compartments also resulted in a significant drop in the objective function compared to the LAG time model. The transit compartments were added sequentially and have been used in literature to account the absorption phase of drugs (28, 38).…”

Section: Discussionmentioning

confidence: 99%

“…To predict the lower concentrations at the delayed absorption phase of enalapril, a lag time model and system of transit compartments were used and analyzed (26). Transit compartments were added in a stepwise approach using erlang distribution method where the optimum number of transit compartments were estimated by adding one transit at a time until there was no further drop in the objective function value of 3.8 or more was observed (27, 28). The mean transit time parameter (MTT1) was estimated and rate transfer through transit compartments was calculated using the expression MTT1 = N+1/KTR, where N is the optimal number of transit compartments and KTR is the rate transfer through these transits (27).…”

Section: Methodsmentioning

confidence: 99%

Simultaneous Semi-Mechanistic Population Pharmacokinetic Modeling Analysis of Enalapril and Enalaprilat Serum and Urine Concentrations From Child Appropriate Orodispersible Minitablets

et al. 2019

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Enalapril is recommended as the first line of therapy and is proven to improve survival rates for treatment of Pediatric Heart Failure; however, an approved drug and child appropriate dosage formulation is still absent. The present analysis was conducted to perform a detailed model informed population pharmacokinetic analysis of prodrug enalapril and its active metabolite enalaprilat in serum and urine. Further, a model informed dosage form population-pharmacokinetic analysis was conducted to evaluate differences in pharmacokinetics of enalapril and its active metabolite enalaprilat when prodrug was administered to 24 healthy adults in a crossover, two periods, two treatments, phase I clinical trial using child-appropriate orodispersible mini-tablets (ODMT) and reference (Renitec®) dosage formulation. A simultaneous semi-mechanistic population-pharmacokinetic model was developed using NONMEM software, which predicted full profile serum and urine concentrations of enalapril and enalaprilat. First-order conditional estimation with interaction was used for parameter estimation. Transit compartments added using Erlang distribution method to predicted enalapril absorption and enalaprilat formation phases. Normalized body weight was identified as covariate related to enalapril volume of distribution. Visual predictive check (VPC) plots and conducted bootstrap analysis validated the model. The data from the two formulations were pooled for population-pharmacokinetic analysis and covariate effect of the formulation was found on mean transit time (MTT1) of enalapril absorption. In addition, data of each formulation were modeled separately and the estimated parameters of each individual administered both formulations were correlated using paired samples Wilcoxon rank test ( p < 0.05 = significant) which also showed only a significant difference ( p = 0.03) in MTT1 i.e., 5 min early appearance of enalapril from ODMT compared to reference tablets. No difference in the pharmacokinetics of active enalaprilat was found from the ODMT compared to the reference formulation. The population pharmacokinetic analysis provided detailed information about the pharmacokinetics of enalapril and enalaprilat, which showed that the ODMT formulation might have similar pharmacodynamic response compared to the reference formulation.

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Pharmacokinetic/Pharmacodynamic Modelling of Venlafaxine

Cited by 15 publications

References 24 publications

Adverse Effects of Antidepressants for Chronic Pain: A Systematic Review and Meta-analysis

Adverse Effects of Antidepressants for Chronic Pain: A Systematic Review and Meta-analysis

Autonomic Dysregulation in Multiple Sclerosis

Simultaneous Semi-Mechanistic Population Pharmacokinetic Modeling Analysis of Enalapril and Enalaprilat Serum and Urine Concentrations From Child Appropriate Orodispersible Minitablets

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