raltegravir-potassium and Colorectal-Neoplasms

Irinotecan toxicity correlates with UGT1A1 activity. We explored whether phenotyping UGT1A1 using a probe approach works better than current genotyping methods.. Twenty-four Asian cancer patients received irinotecan as part of the FOLFIRI regimen. Subjects took raltegravir 400 mg orally and intravenous midazolam 1 mg. Pharmacokinetic analyses were performed using WinNonLin and NONMEM. Genomic DNA was isolated and screened for the known genetic variants in UGT1A1 and CYP3A4/5.. SN-38G/SN-38 AUC ratio correlated well with Raltegravir glucuronide/ Raltegravir AUC ratio (r = 0.784 p<0.01). Midazolam clearance correlated well with irinotecan clearance (r = 0.563 p<0.01). SN-38 AUC correlated well with Log10Nadir Absolute Neutrophil Count (ANC) (r = -0.397 p<0.05). Significant correlation was found between nadir ANC and formation rate constant of raltegravir glucuronide (r = 0.598, P<0.005), but not UGT1A1 genotype.. Raltegravir glucuronide formation is a good predictor of nadir ANC, and can predict neutropenia in East Asian patients. Prospective studies with dose adjustments should be done to develop raltegravir as a probe to optimize irinotecan therapy.. Clinicaltrials.gov NCT00808184.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Camptothecin; Colorectal Neoplasms; Female; Genotype; Glucuronosyltransferase; Humans; Irinotecan; Male; Middle Aged; Phenotype; Raltegravir Potassium

Previous clinical data have shown that raltegravir-based antiretroviral therapy (ART) with fewer drug-drug interactions (DDIs) and adverse events (AEs) is a good regimen in patients with HIV infection who need cancer chemotherapy. There are currently few data on ART regimens that include Integrase inhibitors (INSTIs) other than RAL among this patient subgroup.. We evaluated the safety and efficacy of different kinds of INSTI-based regimens among patients with HIV and concomitant colorectal cancer (CRC) who received antineoplastic agents.. From January 2020 to November 2021, 66 patients were enrolled. The patients were divided into three groups: 20 patients treated with dolutegravir (DTG)/lamivudine (3TC)/tenofovir (TDF) (group I), 24 patients treated with DTG/albuvirtide (ABT) (group II), and 22 patients treated with bictegravir (BIC)/tenofovir alafenamide (TAF)/emtricitabine (FTC) (group III). The majority of AEs during treatment were of grade 1-2. Treatment-related AEs of grade 3-4 occurred in 6 patients (9.09%), and no grade 5 AEs occurred. The most common AEs were nausea (100%) and neutrophils (84.85%) attributed to anticancer agents, and there was no significant difference in the incidence of these AEs among the three groups (P > 0.05). Viral load rebound was not observed among pretreated patients during chemotherapy. The viral load of untreated patients who started their ART concomitant with chemotherapy almost decreased to the lower limit of detection 6 months after ART initiation (only one patient in group III had a viral load of 102 copies/ml). At the 6th month, the CD4 count in group I decreased significantly from baseline (P < 0.05). However, the change in CD4 count was not significant in group II (P = 0.457) or group III (P = 0.748).. DTG- or BIC-containing regimens are good options for patients with HIV and concomitant CRC.

Topics: Amides; Anti-HIV Agents; Colorectal Neoplasms; Emtricitabine; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; Humans; Integrase Inhibitors; Lamivudine; Piperazines; Pyridones; Raltegravir Potassium; Tenofovir