Development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry method to quantify the small molecule inhibitors adagrasib, alectinib, brigatinib, capmatinib, crizotinib, lorlatinib, selpercatinib, and sotorasib in human plasma.

Small molecule inhibitors (SMIs) are increasingly being used in the treatment of non-small cell lung cancer. To support pharmacokinetic research and clinical treatment monitoring, our aim was to develop and validate an ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) assay for quantification of eight SMIs: adagrasib, alectinib, brigatinib, capmatinib, crizotinib, lorlatinib, selpercatinib, and sotorasib. Development of the UPLC-MS/MS assay was done by trying different columns and eluents to optimize peak shape. The assay was validated based on guidelines of the European Medicines Agency. Chromatographic separation was performed with a gradient elution using ammonium formate in water and methanol. Detection was performed using a triple quadrupole tandem mass spectrometer with electrospray ionization. Validation was performed in a range of 10-2500 µg/L for lorlatinib, 25-6250 µg/L for alectinib and crizotinib, 25-10,000 µg/L for capmatinib and selpercatinib, 50-12,500 µg/L for brigatinib, and 100-25,000 µg/L for adagrasib and sotorasib. Imprecision was <8.88% and inaccuracy was <12.5% for all compounds. Seven out of eight compounds were stable for 96 h at room temperature. Sotorasib was stable for 8 h at room temperature. A sensitive and reliable method has been developed to quantify eight SMIs with a single assay, enhancing efficacy and safety of targeted therapies.

Tenofovir Alafenamide Plasma Concentrations Are Reduced in Pregnant Women Living With Human Immunodeficiency Virus (HIV): Data From the PANNA Network.

BACKGROUND: Tenofovir alafenamide (TAF), a prodrug of tenofovir (TFV), is included in the majority of the recommended first-line antiretroviral regimens for patients living with human immunodeficiency virus (HIV), but there are limited data on TAF use in pregnant women. We aimed to examine the plasma pharmacokinetics of TAF and TFV in pregnant women from Europe. METHODS: Pregnant women living with HIV were included from treatment centers across Europe, and intensive pharmacokinetic sampling in the third trimester and postpartum was performed. Pharmacokinetic parameters of TAF and TFV were determined with noncompartmental analysis. The proportion of women with a TAF area under the curve (AUClast) below the target of 53.1 ng∗h/mL was determined. Clinical efficacy and safety outcome parameters were reported. RESULTS: In total, 20 pregnant women living with HIV were included. At the third trimester, geometric mean TAF AUClast and Cmax were decreased by 46% and 52%, respectively, compared with postpartum. TFV AUC0-24h, Cmax, and Ctrough decreased by 33%, 30%, and 34%, respectively. The proportion of women with a TAF AUClast < 53.1 ng∗h/mL was 6% at third trimester and 0% postpartum. One out of 20 women had a viral load > 50 copies/mL at third trimester and no mother-to-child transmission occurred. CONCLUSIONS: TAF plasma concentrations were reduced by about half in women living with HIV during third trimester of pregnancy but remained above the predefined efficacy target in the majority of the pregnant women. TFV concentrations were reduced by approximately 30% during third trimester. Despite the observed exposure decrease, high virologic efficacy was observed in this study.

Rifampicin Transport by OATP1B1 Variants.

Single nucleotide polymorphisms in the OATP1B1 transporter have been suggested to partially explain the large interindividual variation in rifampicin exposure. HEK293 cells overexpressing wild-type (WT) or OATP1B1 variants *1b, *4, *5, and *15 were used to determine the in vitro rifampicin intrinsic clearance. For OATP1B1*5 and *15, a 36% and 42% reduction in intrinsic clearance, respectively, compared to WT was found. We consider that these differences in intrinsic clearance most likely have minor clinical implications.

Inhibitory potential of tuberculosis drugs on ATP-binding cassette drug transporters.

BACKGROUND: Multiple-drug therapy for tuberculosis (TB) and TB-associated co-morbidity increase the likelihood of drug-drug interactions (DDIs). Inhibition of membrane transporters is an important mechanism underlying DDIs. In this study, we assessed the in vitro inhibitory potential of currently used first and second-line TB drugs and of proposed mycobacterial efflux pump inhibitors (EPIs) on the major ABC transporters relevant to drug transport, namely P-gp, BCRP, BSEP and MRP1-5. METHODS: Membrane vesicles isolated from transporter-overexpressing HEK293 cells were used to study the inhibitory action of TB drugs and EPIs on the transport of model substrates [(3)H]-NMQ (P-gp); [(3)H]-E1S (BCRP); [(3)H]-TCA (BSEP); [(3)H]-E217ßG (MRP1, 3 and 4) and [(3)H]-MTX (MRP2 and 5). RESULTS: A strong inhibition (IC50 value <15 µM) was observed for clofazimine (P-gp, BCRP and MRP1), thioridazine (BCRP), timcodar (P-gp, BSEP and MRP1) and SQ109 (P-gp and BCRP). Rifampicin inhibited all transporters, but less potently. CONCLUSIONS: Co-administration of clofazimine, thioridazine, timcodar, SQ109 and possibly rifampicin with drugs that are substrates for the inhibited transporters may lead to DDIs. The mycobacterial EPIs potently inhibited a wider range of human ABC transporters than previously reported. These vesicular transport data are especially valuable considering the current emphasis on development of TB drug regimens.