Investigations on dose proportionality and drug-drug interaction for a fixed-dose combination of trazodone and gabapentin

Picollo, Rossella; Vecchio, A. Del; Calisti, Fabrizio; Dragone, Patrizia; Comandini, Alessandro; Rosignoli, Maria Teresa; Cattaneo, A.; Donath, Frank; Wedemeyer, Ralph-Steven; Todorova-Sanjari, Marina; Warnke, André; Blume, Henning

doi:10.5414/cp203845

Cited by 4 publications

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“…Overall, although the primary efficacy endpoint was not reached in the present RCT, statistically significant results alongside various and consistent trends encourage further investigation of the Trazo/Gaba FDC for NP. Eventually, the results of this RCT are backed up by previous experimental findings, suggesting that synergy between trazodone and gabapentin is likely to occur at the least doses while higher dosages do not bring about additional benefit [16,17,30]. Moreover, we argue that the positive trend toward a mood and sleep quality improvement effect (as indicated by specific validated tools utilized in the present RCT) suggests that the Trazo/Gaba FDC may help improve multidimensional aspects of diabetes such as pain, insomnia, and depressive-like disturbances.…”

Section: Discussionmentioning

confidence: 60%

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Efficacy and Safety of Trazodone and Gabapentin Fixed-Dose Combination in Patients Affected by Painful Diabetic Neuropathy: Randomized, Controlled, Dose-Finding Study

Tesfaye,

Saravanan,

Ehler

et al. 2024

Pain Ther

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Introduction Up to 50% of diabetic patients with neuropathy suffer from chronic pain, namely painful diabetic neuropathy (PDN), an unmet medical need with significant impact on quality of life. Gabapentin is widely used for PDN, albeit with frequent dose-limiting effects. Trazodone, an antidepressant with multi-modal action, has shown promising results when given at low doses as an add-on to gabapentin. Upon previous clinical trials and experimental evidence, a fixed-dose combination (FDC) of both compounds, at low doses, was developed for neuropathic pain. Methods This was a phase II, randomized, double-blind, placebo and reference controlled, dose-finding, multicenter, international, prospective study. Male and female diabetic patients aged 18–75 years and affected by PDN were eligible for enrolment. Patients were randomized (1:1:1:1:2 ratio) to trazodone and gabapentin (Trazo/Gaba) 2.5/25 mg t.i.d. for 8 weeks, Trazo/Gaba 5/50 mg t.i.d. for 8 weeks, Trazo/Gaba 10/100 mg t.i.d. for 8 weeks, gabapentin (Gaba), or placebo (PLB). The aim of the study was to collect preliminary information on the effect of the 3 different FDCs of Trazo/Gaba on pain intensity based on the 11-point numeric rating score (NRS) after 8 weeks of treatment. The secondary objectives were the evaluation of the percentage of responders, neuropathic pain symptoms, anxiety, sleep, quality of life, safety, and tolerability. The primary efficacy endpoint was evaluated with last observation carried out forward (LOCF), using an analysis of covariance (ANCOVA), including treatment and centers as factors and baseline as covariate and applying linear contrast test, excluding the active treatment. Only if the linear contrast test was significant ( p < 0.05), the step-down Dunnett test would be used to determine the minimum effective dose significantly different from PLB. If linearity was not verified, an adjusted ANCOVA model and comparisons with Dunnett test were performed. Before the application of the ANCOVA model, the non-significance of interaction treatment per baseline was verified. Results A total of 240 patients were included in the modified intention-to-treat (m-ITT) population: 39 in Trazo/Gaba 2.5/25 mg, 38 in Trazo/Gaba 5/50 mg, 37 in Trazo/Gaba 10/100 mg, 83 in PLB, and 43 in Gaba. After 8 weeks of treatment, changes of the average daily pain score based on the 11-point NRS from baseline were − 2.52 ± 2.31 in Trazo/Gaba 2.5/25 mg group, − 2.24 ± 1.96 in Trazo/Gaba 5/50 mg group, − 2.46 ± 2.12 in Trazo/Gaba 10/100 mg group, − 1.92 ± 2.21 in Gaba group, and − 2.02 ± 1.95 in the PLB group. The linear contrast test did not result in significant differences ( p > 0.05) among treatment groups. Consequently, the minimum effective dose against PLB was not determined. The multiple comparison with Dunnett adjustment did not show any statistically significant differences vs. PLB after 8 weeks of treatment: Trazo/Gaba 2....

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Section: Discussionmentioning

confidence: 60%

“…Consequently, a phase I trial was performed to assess dose proportionality, drug–drug interactions and safety of different Trazo/Gaba FDCs in healthy volunteers [ 17 ]. The proportionality for trazodone at doses of 2.5–30 mg and for gabapentin at doses of 25–300 mg was investigated for the first time.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of Trazodone and Gabapentin Fixed-Dose Combination in Patients Affected by Painful Diabetic Neuropathy: Randomized, Controlled, Dose-Finding Study

Tesfaye,

Saravanan,

Ehler

et al. 2024

Pain Ther

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“…In 2021, in the single-center, open-label, randomized, 5-period cross-over trial, an interaction between the newer antiepileptic drug, gabapentin (25-300 mg), and trazodone (2.5-10 mg) was evaluated in healthy volunteers following single dose fasted administration. In no case pharmacokinetic interactions were evident in terms of the plasma AUC or C max (Ruggieri et al, 2021).…”

Section: Pharmacokinetic Interactions Between Antiepielptic and Antid...mentioning

confidence: 89%

Comorbid epilepsy and depression—pharmacokinetic and pharmacodynamic drug interactions

Miziak

Czuczwar²,

Pluta³

2022

Front. Pharmacol.

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Background: Major depressive disorder may be encountered in 17% of patients with epilepsy and in patients with drug-resistant epilepsy its prevalence may reach 30%. This indicates that patients with epilepsy may require antidepressant treatment.Purpose: Both pharmacodynamic and pharmacokinetic interactions between antiepileptic (antiseizure) and antidepressant drugs have been reviewed. Also, data on the adverse effects of co-administration of antiepileptic with antidepressant drugs have been added. This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology.Methods: The review of relevant literature was confined to English-language publications in PUBMED databases. Table data show effects of antidepressants on the seizure susceptibility in experimental animals, results of pharmacodynamic interactions between antiepileptic and antidepressant drugs mainly derived from electroconvulsions in mice, as well as results concerning pharmacokinetic interactions between these drugs in clinical conditions.Conclusion: Antidepressant drugs may exert differentiated effects upon the convulsive threshold which may differ in their acute and chronic administration. Animal data indicate that chronic administration of antidepressants could reduce (mianserin, trazodone) or potentiate the anticonvulsant activity of some antiepileptics (fluoxetine, reboxetine, venlafaxine). There are also examples of neutral interactions (milnacipran).

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“…During the development of the method, we verified that no drug–drug PK interaction occurred in mice and the lack of drug–drug PK interaction, which was consistent with published human data. 34 That was somehow expected because gabapentin is eliminated from the systemic circulation as unchanged drug by renal excretion and is not appreciably metabolized in animal species and humans.…”

Section: Discussionmentioning

confidence: 99%

PK/PD analysis of trazodone and gabapentin in neuropathic pain rodent models: Translational PK‐PD modeling from nonclinical to clinical development

Oggianu

Garrone

Fiorentini³

et al. 2023

Clinical Translational Sci

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A pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the time course of writhings after intraperitoneal injection of acetic acid in mice. The model was applied to investigate the antinociceptive effect of trazodone and gabapentin alone and in combination. Writhings time course was described by a transit compartment model with the delay due to the transit of the acetic acid being represented by a chain of intermediate compartments. In the drug‐treated animals, the number of writhings decreases according to a k2 factor linking drug concentration and antinociceptive effect. Compounds' potency parameters were 10.9 and 0.0459 L/μmoles/min for trazodone and gabapentin, respectively, indicating a much higher in vivo potency of trazodone in the PD writhing test. The PK/PD parameters were used to simulate the expected writhing counts in mice at combined doses without efficacy alone, assuming pharmacological additivity. Simulation results indicated that, at low dose combinations, experimental data were mostly below the simulated writhings median, suggesting possible synergic effect. Such hypothesis was tested by adding the γ parameter in the PK/PD model to represent the deviation from the assumption of no‐interaction, leading to a reduction of the objective function compared to the additive model. On this basis, several simulations were performed to identify possible starting dose combinations of trazodone and gabapentin in humans, by selecting doses yielding systemic exposures close to those being synergic in the mouse. Simulations indicated that doses of 50–100 mg trazodone could enhance gabapentin antinociceptive effect in humans, supporting the development of a low dose combination for optimal analgesia treatment.

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Investigations on dose proportionality and drug-drug interaction for a fixed-dose combination of trazodone and gabapentin

Cited by 4 publications

References 0 publications

Efficacy and Safety of Trazodone and Gabapentin Fixed-Dose Combination in Patients Affected by Painful Diabetic Neuropathy: Randomized, Controlled, Dose-Finding Study

Efficacy and Safety of Trazodone and Gabapentin Fixed-Dose Combination in Patients Affected by Painful Diabetic Neuropathy: Randomized, Controlled, Dose-Finding Study

Comorbid epilepsy and depression—pharmacokinetic and pharmacodynamic drug interactions

PK/PD analysis of trazodone and gabapentin in neuropathic pain rodent models: Translational PK‐PD modeling from nonclinical to clinical development

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