Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats.

Agnieszka Karbownik,Edmund Grześkowiak,Radosław Jaźwiec,Tomasz Grabowski,Edyta Szałek,Danuta Szkutnik-Fiedler,Anna Wolc,Joanna Stanisławiak-Rudowicz

doi:10.3390/pharmaceutics13122172

Abstract

A combination of the tyrosine kinase inhibitor—sorafenib—and the opioid analgesic—morphine—can be found in the treatment of cancer patients. Since both are substrates of P-glycoprotein (P-gp), and sorafenib is also an inhibitor of P-gp, their co-administration may affect their pharmacokinetics, and thus the safety and efficacy of cancer therapy. Therefore, the aim of this study was to evaluate the potential pharmacokinetic drug–drug interactions between sorafenib and morphine using an animal model. The rats were divided into three groups that Received: sorafenib and morphine (ISOR+MF), sorafenib (IISOR), and morphine (IIIMF). Morphine caused a significant increase in maximum plasma concentrations (Cmax) and the area under the plasma concentration–time curves (AUC0–t, and AUC0–∞) of sorafenib by 108.3 (p = 0.003), 55.9 (p = 0.0115), and 62.7% (p = 0.0115), respectively. Also, the Cmax and AUC0–t of its active metabolite—sorafenib N-oxide—was significantly increased in the presence of morphine (p = 0.0022 and p = 0.0268, respectively). Sorafenib, in turn, caused a significant increase in the Cmax of morphine (by 0.5-fold, p = 0.0018). Moreover, in the presence of sorafenib the Cmax, AUC0–t, and AUC0–∞ of the morphine metabolite M3G increased by 112.62 (p < 0.0001), 46.82 (p = 0.0124), and 46.78% (p = 0.0121), respectively. Observed changes in sorafenib and morphine may be of clinical significance. The increased exposure to both drugs may improve the response to therapy in cancer patients, but on the other hand, increase the risk of adverse effects.

Highlights

All the data were expressed as the arithmetic mean value ± standard deviation (SD)
When sorafenib was co-administered with morphine (ISOR+MF group), the Cmax, AUC0–t, and AUC0–∞ of sorafenib significantly increased by 108.3 (p = 0.003), 55.9 (p = 0.0115), and 62.7% (p = 0.0115), respectively (Table 1, Figure 1)
Lower ka and CL/F values were observed for sorafenib in the group of rats receiving both drugs when compared to the sorafenib treatment group alone

Summary

Introduction

About 50% of cancer patients undergoing active anti-cancer therapy and 90% of patients in the advanced stages experience severe pain [1]. In the clinical practice of cancer therapies, it can be expected that a combination of tyrosine kinase inhibitors (TKIs), such as sorafenib, and opioid analgesics, including morphine, are used, which, according to the WHO guidelines, is the first-choice opioid in the relief of cancer pain [2]. Sorafenib belongs to the group of multi-kinase inhibitors, showing antiproliferative activity of cancer cells and anti-angiogenic properties [3]. Targeted therapy, an example of which is sorafenib, is the most promising form of pharmacotherapy among 4.0/).

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