A comparative study for detecting CYP3A induction by CYP3A probe drugs and endogenous markers in cynomolgus monkeys

Abstract

CYP3A probe drugs such as midazolam and endogenous markers, and plasma 4β‐hydroxycholesterol (4β‐OHC) and urinary 6β‐hydroxycortisol‐to‐cortisol ratios (6β‐OHC/C) have been used as markers of CYP3A induction in cynomolgus monkeys, as with humans. However, there is limited information on their sensitivity and ability to detect CYP3A induction, as most studies were evaluated only at a high dose of the inducer, rifampicin (RIF; 20 mg/kg). In the present study, the CYP3A induction by RIF over a range doses of 0.2, 2 and 20 mg/kg (n = 4) was examined using CYP3A probe drugs (midazolam, triazolam and alprazolam) and the plasma and urinary endogenous CYP3A markers (4β‐OHC and 6β‐OHC/C). The sensitivity and relationship for detecting CYP3A induction was compared among the markers. Four days repeated oral administration of rifampicin to cynomolgus monkeys reduced the area under the plasma concentration–time curve of all CYP3A probe drugs in a rifampicin dose‐dependent manner. Although the endogenous CYP3A markers (4β‐OHC and 6β‐OHC/C) were also changed for the middle (2 mg/kg) and high (20 mg/kg) doses of rifampicin, the fold‐changes were relatively small, and CYP3A induction could not be detected at the lowest dose of rifampicin (0.2 mg/kg). In conclusion, CYP3A probe drugs are more sensitive for detecting CYP3A induction than endogenous CYP3A markers in cynomolgus monkeys, even for a short experimental period.

Absence of OATP1B (Organic Anion–Transporting Polypeptide) Induction by Rifampin in Cynomolgus Monkeys: Determination Using the Endogenous OATP1B Marker Coproporphyrin and Tissue Gene Expression

“…The final version may differ from this version. and OATP1B, respectively (Diczfalusy et al, 2011, Kasichayanula et al, 2014, Li et al, 2014, Tahara et al, 2019, Takehara et al, 2019, Gu et al, 2020. Therefore, 4βHC, CPI, and CPIII were selected as in vivo probes of CYP3A and OATP1B activities, and we studied the day-to-day change from predose plasma levels and throughout the entire study with the strong PXR activator RIF.…”

“…RIF is also a wellknown inhibitor of OATP1B and is associated with many DDIs. The pharmaceutical industry is working toward the use of putative endogenous biomarkers, such as 4βHC in place of probe drugs for CYP3A induction investigation to avoid unnecessary administration of drugs to subjects (Diczfalusy et al, 2011, Kasichayanula et al, 2014, Li et al, 2014, Mao et al, 2017, Tahara et al, 2019. The in vivo induction potential of a NME could be investigated in preclinical animal toxicity and early clinical pharmacokinetic studies with repeated dosing using endogenous biomarkers.…”

Midazolam oxidation in cattle liver microsomes: The role of cytochrome P450 3A

“…It is also the drug most commonly used to evaluate CYP3A phenotype (van Dick et al, 2019). Based on these properties, MDZ oxidation has been considered as a CYP3A‐dependent catalytic activity in dog, cat, pig, sheep and cynomolgus monkey (Kuroha et al, 2002; Shah et al, 2006; Hu, 2015; Stuchlíková et al, 2015; Tahara et al, 2018).…”

Induction of Human Intestinal and Hepatic Organic Anion Transporting Polypeptides: Where Is the Evidence for Its Relevance in Drug-Drug Interactions?

“…It is accepted that RIF induces CYP3A4 and ABC transporters via the PXR, whereas CBZ (a relatively weak PXR agonist vs. RIF) manifests a somewhat different induction signature via other nuclear receptors such as the constitutive androstane receptor (CAR, NR1I3) (Faucette et al, 2007;Kim et al, 2010). In fact, RIF has been studied extensively as an inducer in vitro and in animals (humanized rodents and nonhuman primate), and clinical assessment has involved the use of CYP3A biomarkers (e.g., 6b-hydroxycortisol-to-cortisol urine ratio, plasma 4bhydroxycholesterol) as well as CYP3A (e.g., midazolam) and Pgp (e.g., digoxin, dabigatran etexilate) probe drugs (Greiner et al, 1999;Rae et al, 2001;Peng et al, 2011;Li et al, 2014;Henderson et al, 2019;Tahara et al, 2019;Yamazaki et al, 2019). Because various statins are accepted clinical probes for the study of SLCO1B1 genotype-phenotype associations and inhibitory OATP DDIs, it is not surprising that there are numerous reports describing the impact of multidose RIF and CBZ on their PK (Kyrklund et al, 2003;Ucar et al, 2004;Backman et al, 2005;Chung et al, 2006;Lutz et al, 2018a,b).…”

“…In recent years, the cynomolgus monkey has increasingly been used as a model to investigate PXR-mediated induction of CYP3A by agents such as RIF. This is because monkey PXR is highly homologous to the human ortholog (96%) and cynomolgus monkey CYP3A is inducible by RIF both in vitro and in vivo (Kim et al, 2010;Li et al, 2014;Tahara et al, 2019). In fact, the RIF dose response curves for CYP3A4 induction in plated cynomolgus monkey and human primary hepatocytes are comparable (Kim et al, 2010).…”