Severe hypokalemia due to a possible drug-drug interaction between vinblastine and antiretrovirals in a HIV-infected patient with Hodgkin's lymphoma.

A 60-year-old HIV-1 infected woman on antiretroviral therapy (emtricitabine/tenofovir, and ritonavir-boosted atazanavir) developed Hodgkin's lymphoma. The patient initiated ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) chemotherapy and presented with neutropenia and severe hypokalemia. Hypokalemia was considered as part of a proximal tubular renal dysfunction, and other causes of hypokalemia were excluded. Due to suspicion of drug--drug interactions between antiretrovirals and vinblastine, ritonavir-boosted atazanavir was switched to dolutegravir and the patient continued emtricitabine/tenofovir. In the subsequent ABVD cycles, no neutropenia or hypokalemia were observed. Vinblastine is metabolized by the hepatic P450 cytochrome isoenzyme CYP3A4, therefore, concomitant administration with protease inhibitors may increase plasma levels of vinblastine. Vinblastine is also a substrate and inhibitor of multidrug resistance-associated protein 2 (MRP2) transporter in the proximal renal tubule. Inhibition of this renal transporter could increase tenofovir renal toxicity. Our hypothesis is that the hypokalemia could be a result of a tenofovir-mediated tubular damage triggered by the increased vinblastine serum levels secondary to a CYP3A4 inhibition by ritonavir. To the best of our knowledge, this is the first report of severe hypokalemia and proximal tubular renal dysfunction as a result of a possible drug-drug interaction between vinblastine, tenofovir and ritonavir-boosted atazanavir.

Pharmacokinetic evaluation of gemcitabine hydrochloride for the treatment of cervical cancer.

INTRODUCTION: Cervical cancer is the third most prevalent cancer in females worldwide. When advanced, the disease requires primary radiation concurrent with chemotherapy. However, chemotherapy alone is the standard treatment for recurrent/persistent/metastatic disease. AREAS COVERED: Areas covered in this review include the treatment of advanced cervical cancer with gemcitabine as radiosensitizer, either alone or in combination with cisplatin. The use of gemcitabine for recurrent/persistent/metastatic cervical cancer is also reviewed. EXPERT OPINION: Statistically significantly better survival rates are achieved with cisplatin doublets against cisplatin alone, in the management of recurrent/persistent/metastatic cervical cancer. The choice of the cisplatin doublet with paclitaxel, vinorelbine, gemcitabine and topotecan arms should be based on physician preference, pre-existing morbidity and patient-related factors. In advanced disease, a recently reported Phase III trial establishes the novel regimen of concurrent gemcitabine plus cisplatin and external radiation, followed by brachytherapy and two adjuvant 21-day cycles of gemcitabine plus cisplatin, as significantly improving survival outcomes when compared with the current standard of care. The increased acute toxicity of this regimen is clear; however, this should not deter its incorporation into clinical practice, in that the toxicity is predictable and manageable; nevertheless, the occurrence of late toxicity and survival at longer follow-up time are reasonable concerns in this regimen.

An HPLC-UV method for the measurement of permeability of marker drugs in the Caco-2 cell assay

The Caco-2 cell line has been used as a model to predict the in vitro permeability of the human intestinal barrier. The predictive potential of the assay relies on an appropriate in-house validation of the method. The objective of the present study was to develop a single HPLC-UV method for the identification and quantitation of marker drugs and to determine the suitability of the Caco-2 cell permeability assay. A simple chromatographic method was developed for the simultaneous determination of both passively (propranolol, carbamazepine, acyclovir, and hydrochlorothiazide) and actively transported drugs (vinblastine and verapamil). Separation was achieved on a C18 column with step-gradient elution (acetonitrile and aqueous solution of ammonium acetate, pH 3.0) at a flow rate of 1.0 mL/min and UV detection at 275 nm during the total run time of 35 min. The method was validated and found to be specific, linear, precise, and accurate. This chromatographic system can be readily used on a routine basis and its utilization can be extended to other permeability models. The results obtained in the Caco-2 bi-directional transport experiments confirmed the validity of the assay, given that high and low permeability profiles were identified, and P-glycoprotein functionality was established.

An HPLC-UV method for the measurement of permeability of marker drugs in the Caco-2 cell assay.

The Caco-2 cell line has been used as a model to predict the in vitro permeability of the human intestinal barrier. The predictive potential of the assay relies on an appropriate in-house validation of the method. The objective of the present study was to develop a single HPLC-UV method for the identification and quantitation of marker drugs and to determine the suitability of the Caco-2 cell permeability assay. A simple chromatographic method was developed for the simultaneous determination of both passively (propranolol, carbamazepine, acyclovir, and hydrochlorothiazide) and actively transported drugs (vinblastine and verapamil). Separation was achieved on a C18 column with step-gradient elution (acetonitrile and aqueous solution of ammonium acetate, pH 3.0) at a flow rate of 1.0 mL/min and UV detection at 275 nm during the total run time of 35 min. The method was validated and found to be specific, linear, precise, and accurate. This chromatographic system can be readily used on a routine basis and its utilization can be extended to other permeability models. The results obtained in the Caco-2 bi-directional transport experiments confirmed the validity of the assay, given that high and low permeability profiles were identified, and P-glycoprotein functionality was established.