PMID- 37361220
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230701
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 14
DP  - 2023
TI  - Pharmacokinetic interaction of voriconazole and clarithromycin in Pakistani 
      healthy male volunteers: a single dose, randomized, crossover, open-label study.
PG  - 1134803
LID - 10.3389/fphar.2023.1134803 [doi]
LID - 1134803
AB  - Background: Voriconazole an antifungal drug, has a potential for drug-drug 
      interactions (DDIs) with administered drugs. Clarithromycin is a Cytochromes P450 
      CYP (3A4 and 2C19) enzyme inhibitor, and voriconazole is a substrate and 
      inhibitor of these two enzymes. Being a substrate of the same enzyme for 
      metabolism and transport, the chemical nature and pKa of both interacting drugs 
      make these drugs better candidates for potential pharmacokinetic drug-drug 
      interactions (PK-DDIs). This study aimed to evaluate the effect of clarithromycin 
      on the pharmacokinetic profile of voriconazole in healthy volunteers. Methods: A 
      single oral dose, open-label, randomized, crossover study was designed for 
      assessing PK-DDI in healthy volunteers, consisting of 2 weeks washout period. 
      Voriconazole, either alone (2 mg x 200 mg, tablet, P/O) or along with 
      clarithromycin (voriconazole 2 mg x 200 mg, tablet + clarithromycin 500 mg, 
      tablet, P/O), was administered to enrolled volunteers in two sequences. The blood 
      samples (approximately 3 cc) were collected from volunteers for up to 24 h. 
      Plasma concentrations of voriconazole were analyzed by an isocratic, 
      reversed-phase high-performance-liquid chromatography ultraviolet-visible 
      detector (RP HPLC UV-Vis) and a non-compartmental method. Results: In the present 
      study, when voriconazole was administered with clarithromycin versus administered 
      alone, a significant increase in peak plasma concentration (Cmax) of voriconazole 
      by 52% (geometric mean ratio GMR: 1.52; 90% CI 1.04, 1.55; p = 0.000) was 
      observed. Similarly, the area under the curve from time zero to infinity 
      (AUC(0-infinity)) and the area under the concentration-time curve from time zero to 
      time-t (AUC(0-t)) of voriconazole also significantly increased by 21% (GMR: 1.14; 
      90% CI 9.09, 10.02; p = 0.013), and 16% (GMR: 1.15; 90% CI 8.08, 10.02; p = 
      0.007), respectively. In addition, the results also showed a reduction in the 
      apparent volume of distribution (Vd) by 23% (GMR: 0.76; 90% CI 5.00, 6.20; p = 
      0.051), and apparent clearance (CL) by 13% (GMR: 0.87; 90% CI 41.95, 45.73; p = 
      0.019) of voriconazole. Conclusion: The alterations in PK parameters of 
      voriconazole after concomitant administration of clarithromycin are of clinical 
      significance. Therefore, adjustments in dosage regimens are warranted. In 
      addition, extreme caution and therapeutic drug monitoring are necessary while 
      co-prescribing both drugs. Clinical Trial Registration: clinicalTrials.gov, 
      Identifier NCT05380245.
CI  - Copyright (c) 2023 Mushtaq, Fatima, Ahmad, Mohamed Ibrahim, Faheem and Shah.
FAU - Mushtaq, Mehwish
AU  - Mushtaq M
AD  - Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan.
AD  - Department of Pharmacy, University of Peshawar, Peshawar, Pakistan.
FAU - Fatima, Kshaf
AU  - Fatima K
AD  - University Medical and Dental College, The University of Faisalabad, Faisalabad, 
      Pakistan.
FAU - Ahmad, Aneeqa
AU  - Ahmad A
AD  - Punjab Medical College, Faisalabad Medical University, Faisalabad, Pakistan.
FAU - Mohamed Ibrahim, Osama
AU  - Mohamed Ibrahim O
AD  - College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates.
AD  - Faculty of Pharmacy, Cairo University, Cairo, Egypt.
FAU - Faheem, Muhammad
AU  - Faheem M
AD  - Department of Pharmacy, University of Swabi, Swabi, Pakistan.
FAU - Shah, Yasar
AU  - Shah Y
AD  - Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan.
LA  - eng
SI  - ClinicalTrials.gov/NCT05380245
PT  - Journal Article
DEP - 20230609
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC10288581
OTO - NOTNLM
OT  - clarithromycin (CLRM)
OT  - clinical significance
OT  - crossover
OT  - open-label
OT  - pharmacokinetic drug-drug interaction (PK-DDI)
OT  - randomized
OT  - voriconazole (voriz)
OT  - washout period
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/06/26 19:07
MHDA- 2023/06/26 19:08
PMCR- 2023/06/09
CRDT- 2023/06/26 12:49
PHST- 2022/12/30 00:00 [received]
PHST- 2023/04/26 00:00 [accepted]
PHST- 2023/06/26 19:08 [medline]
PHST- 2023/06/26 19:07 [pubmed]
PHST- 2023/06/26 12:49 [entrez]
PHST- 2023/06/09 00:00 [pmc-release]
AID - 1134803 [pii]
AID - 10.3389/fphar.2023.1134803 [doi]
PST - epublish
SO  - Front Pharmacol. 2023 Jun 9;14:1134803. doi: 10.3389/fphar.2023.1134803. 
      eCollection 2023.