Para-aminosalicylic acid significantly reduced tenofovir exposure in human subjects: Mismatched findings from in vitro to in vivo translational research

Parvez M. M., Kalkisim S., Nguyen P. T. T., Jung J. A., Park J., Ghim J., ...Daha Fazla

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, cilt.88, sa.3, ss.1159-1169, 2022 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 88 Sayı: 3
  • Basım Tarihi: 2022
  • Doi Numarası: 10.1111/bcp.15056
  • Dergi Adı: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.1159-1169
  • Anahtar Kelimeler: drug-drug interactions, organic anion transporter, para-aminosalicylic acid, pharmacokinetics, tenofovir, DISOPROXIL FUMARATE, ORGANIC ANION, INTESTINAL-ABSORPTION, DRUG-INTERACTIONS, PHARMACOKINETICS, RESISTANT, TRANSPORTERS, TUBERCULOSIS, PREDICTION, RIFAMPICIN
  • Hacettepe Üniversitesi Adresli: Evet

Özet

Aims Tenofovir and para-aminosalicylic acid (PAS) may be coprescribed to treat patients with concomitant infections of human immunodeficiency virus and Mycobacterium tuberculosis bacteria. Both drugs are known to have remarkable renal uptake transporter-mediated clearance. Owing to the lack of clinical studies on drug-drug interaction between the 2 drugs, we conducted a translational clinical study to investigate the effect of PAS on tenofovir pharmacokinetics (PK). Methods Initially, we studied in vitro renal uptake transporter-mediated drug-drug interactions using stably transfected cells with human organic anion transporters (OAT1 and OAT3). Later, we estimated clinical drug interactions using static and physiologically based PK modelling. Finally, we investigated the effects of PAS-calcium formulation (PAS-Ca) on tenofovir disoproxil fumarate PK in healthy male Korean subjects. Results PAS inhibited OAT1- and OAT3-mediated tenofovir uptake in vitro. The physiologically based PK drug-drug interaction model suggested a 1.26-fold increase in tenofovir peak plasma concentration when coadministered with PAS. By contrast, an open-label, randomized, crossover clinical trial evaluating the effects of PAS-Ca on tenofovir PK showed significantly altered geometric mean ratio (90% confidence intervals) of maximum plasma concentration (C-max) and area under the curve (AUC(0-inf)) by 0.33 (0.28-0.38) and 0.29 (0.26-0.33), respectively. Conclusion Our study findings suggest that the PAS-Ca formulation significantly reduced systemic exposure to tenofovir through an unexplained mechanism, which was contrary to the initial prediction. Caution should be exercised while predicting in vivo PK profiles from in vitro data, particularly when there are potential confounders such as pharmaceutical interactions.