Pre-absorption physicochemical compatibility assessment of 8-drug metabolic cocktail

Tye, Ching Kim; Wang, Zhanbin; Dockens, Randy C.; Vakkalagadda, Blisse; Wang, Chunlei; Zhang, Yingru; Su, Ching; Hageman, Michael J.

doi:10.1016/j.ijpharm.2016.06.028

Cited by 5 publications

(9 citation statements)

References 43 publications

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“…For instance, montelukast used as a probe for CYP2C8 is also cleared up by hepatic OATP‐mediated transporters, potentially confounding results 27 . However, the cocktail approach is in alignment with Food and Drug Administration guidance for evaluation of CYP enzyme‐ and transporter‐mediated DDIs, and all probe substrates were shown to be compatible in a previous study 20,22 …”

Section: Discussionmentioning

confidence: 93%

Open‐label, drug–drug interaction study between the HIV‐1 maturation inhibitor GSK3640254 and a metabolic probe cocktail in healthy participants

Zhang

Johnson²,

Joshi³

et al. 2023

Brit J Clinical Pharma

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Aims GSK3640254 (GSK'254) is an HIV‐1 maturation inhibitor with pharmacokinetics (PK) supporting once‐daily dosing. GSK'254 will be co‐administered with cytochrome P450 enzyme substrates and drug transporters, including other antiretrovirals, in people living with HIV‐1 (PLWH). Methods In this open‐label study, healthy participants received a single dose of a cocktail of eight cytochrome P450 and transporter probe substrates on Day 1, followed by a 10‐day washout before receiving GSK'254 200 mg once daily from Days 11 to 20 and a single dose of cocktail + GSK'254 200 mg on Day 21. Geometric least‐squares mean ratios and 90% confidence intervals were obtained using linear mixed‐effects models. Adverse events (AEs) were monitored. Results Of 20 participants enrolled, 19 completed the study. Plasma concentrations of all cocktail substrates were generally similar with or without GSK'254 co‐administration. All 90% confidence intervals around geometric least‐squares mean ratios for cocktail substrate PK parameters indicated no to weak interactions. Steady‐state plasma GSK'254 concentrations were achieved by Day 17 and maintained through Day 21. Nine participants (45%) reported 17 AEs; most (88%) were grade 1. Two grade 2 treatment‐related AEs (maculopapular rash [leading to withdrawal] and papular rash) were reported during GSK'254 administration alone. Conclusions Co‐administration of GSK'254 with a metabolic probe cocktail in healthy participants indicated very low risk of clinically relevant effect on PK of any substrates or associated metabolites. No new safety/tolerability concerns were identified. These results support ongoing phase IIb and planned phase III studies of GSK'254 in people living with HIV‐1.

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Section: Discussionmentioning

confidence: 93%

Open‐label, drug–drug interaction study between the HIV‐1 maturation inhibitor GSK3640254 and a metabolic probe cocktail in healthy participants

Zhang

Johnson²,

Joshi³

et al. 2023

Brit J Clinical Pharma

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“…For example, Tye et al. ( 2016 ) systemically evaluated the physicochemical properties of an eight-drug metabolic cocktail and thereby recommended the progression of its suitable oral formulations into a clinical validation study. Another example can be found in our previous study on the pre-absorption risks of Morin, one of the most important flavonoid compounds (Li et al., 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…Particularly, the physicochemical properties of drugs and their stability in the gastrointestinal tract are fundamental to the selection of oral formulation strategy (Sun et al, 2012;Jambhekar & Breen, 2013). For example, Tye et al (2016) systemically evaluated the physicochemical properties of an eight-drug metabolic cocktail and thereby recommended the progression of its suitable oral formulations into a clinical validation study. Another example can be found in our previous study on the pre-absorption risks of Morin, one of the most important flavonoid compounds (Li et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Rational formulation engineering of fraxinellone utilizing 6-O-α-D-maltosyl-β-cyclodextrin for enhanced oral bioavailability and hepatic fibrosis therapy

Feng

Yang

et al. 2021

Drug Delivery

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Although Fraxinellone (Frax) isolated from Dictamnus albus L. possessed excellent anti-hepatic fibrosis activity, oral administration of Frax suffered from the inefficient therapeutic outcome in vivo due to negligible oral absorption. At present, the oral formulation of Frax is rarely exploited. For rational formulation design, we evaluated preabsorption risks of Frax and found that Frax was rather stable while poorly dissolved in the gastrointestinal tract (78.88 μg/mL), which predominantly limited its oral absorption. Further solubility test revealed the outstanding capacity of cyclodextrin derivatives (CDs) to solubilize Frax (6.8–12.8 mg/mL). This led us to study the inclusion complexes of Frax with a series of CDs and holistically explore their drug delivery performance. Characterization techniques involving 1 H-NMR, FT-IR, DSC, PXRD, and molecular docking confirmed the most stable binding interactions when Frax complexed with 6-O-α-D-maltosyl-β-cyclodextrin (G 2 -β-CD-Frax). Notably, G 2 -β-CD-Frax exhibited the highest solubilizing capacity, fast dissolution rate, and superior Caco-2 cell internalization with no obvious toxicity. Pharmacokinetic studies demonstrated markedly higher oral bioavailability of G 2 -β-CD-Frax (5.8-fold that of free drug) than other Frax-CDs. Further, long-term administration of G 2 -β-CD-Frax (5 mg/kg) efficiently inhibited CCl 4 -induced hepatic fibrosis in the mouse without inducing any toxicity. Our results will inspire the continued advancement of optimal oral Frax formulations for anti-fibrotic therapy.

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“…The metabolic cocktail approach is well established for the assessment of CYP effects, but until recently there were no clinically evaluated cocktails covering both CYP and major transporter pathways such as P-gp and OATP. A novel eight-probe cocktail has now been developed [ 19 ] that includes substrate probes for six CYP enzymes—CYP1A2 (caffeine), CYP2D6 (metoprolol), CYP2C8 (montelukast), CYP2C19 (flurbiprofen), CYP2C19 (omeprazole), and CYP3A4 (midazolam)—plus probes for P-gp (digoxin) and OATP (pravastatin). These eight common clinical agents have well-characterized and acceptable safety profiles, and have shown acceptable pre-absorption compatibility in vitro [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…A novel eight-probe cocktail has now been developed [ 19 ] that includes substrate probes for six CYP enzymes—CYP1A2 (caffeine), CYP2D6 (metoprolol), CYP2C8 (montelukast), CYP2C19 (flurbiprofen), CYP2C19 (omeprazole), and CYP3A4 (midazolam)—plus probes for P-gp (digoxin) and OATP (pravastatin). These eight common clinical agents have well-characterized and acceptable safety profiles, and have shown acceptable pre-absorption compatibility in vitro [ 19 ]. Here, we report the use of this eight-agent cocktail to assess in vivo the drug–drug interaction potential of steady-state DCV, ASV, and BCV, administered as a fixed-dose co-formulation to healthy volunteers without HCV infection.…”

Section: Introductionmentioning

confidence: 99%

Effects of a Fixed-Dose Co-Formulation of Daclatasvir, Asunaprevir, and Beclabuvir on the Pharmacokinetics of a Cocktail of Cytochrome P450 and Drug Transporter Substrates in Healthy Subjects

et al. 2017

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BackgroundA fixed-dose combination of daclatasvir (DCV; hepatitis C virus NS5A inhibitor), asunaprevir (ASV; non-structural protein 3 inhibitor), and beclabuvir (BCV; non-structural protein 5B inhibitor) is approved in Japan for hepatitis C virus genotype 1.ObjectiveThe objective of this study was to assess the combination’s drug–drug interaction potential in vivo using a validated cocktail of eight cytochrome P450 (CYP) and transporter probes.MethodsWe conducted an open-label single-sequence study in healthy adults (n = 20) given single-dose caffeine (CYP1A2 substrate), metoprolol (CYP2D6), flurbiprofen (CYP2C9), montelukast (CYP2C8), omeprazole (CYP2C19), midazolam (CYP3A4), digoxin (P-glycoprotein), and pravastatin (organic anion-transporting polypeptide), alone or with steady-state twice-daily DCV/ASV/BCV 30/200/75 mg (with or without additional BCV 75 mg to adjust for higher exposure in hepatitis C virus infection).ResultsDaclatasvir/asunaprevir/beclabuvir did not affect CYP1A2, CYP2C8, or CYP2C9; the probe maximum observed concentration and area under the concentration–time curve extrapolated to infinite time geometric mean ratios and 90% confidence intervals were all within the 0.8–1.25 bioequivalence range. Beclabuvir showed moderate dose-dependent CYP2C19 induction; omeprazole maximum observed concentration and area under the concentration–time curve from 0 to the last quantifiable concentration were lower with additional BCV [geometric mean ratio 0.36 (90% confidence interval 0.23–0.55) and 0.34 (0.25–0.46), respectively] than without [0.57 (0.42–0.78), 0.48 (0.39–0.59)]. Weak-to-moderate CYP3A4 induction was observed, plus weak CYP2D6, P-glycoprotein, and organic anion-transporting polypeptide inhibition [maximum observed concentration and area under the concentration–time curve extrapolated to infinite time without additional BCV: midazolam 0.57 (0.50–0.65), 0.53 (0.47–0.60); metoprolol 1.40 (1.20–1.64), 1.71 (1.49–1.97); digoxin 1.23 (1.12–1.35), 1.23 (1.17–1.29); pravastatin 2.01 (1.63–2.47), 1.68 (1.43–1.97)].ConclusionsNo dose adjustments with DCV/ASV/BCV are indicated for CYP1A2, CYP2C8, CYP2C9, or P-glycoprotein substrates. CYP3A4, CYP2D6, and OATP substrates should be co-administered with caution. Co-administration with agents solely metabolized by CYP2C19 is not recommended.Electronic supplementary materialThe online version of this article (10.1007/s40268-017-0222-8) contains supplementary material, which is available to authorized users.

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Pre-absorption physicochemical compatibility assessment of 8-drug metabolic cocktail

Cited by 5 publications

References 43 publications

Open‐label, drug–drug interaction study between the HIV‐1 maturation inhibitor GSK3640254 and a metabolic probe cocktail in healthy participants

Open‐label, drug–drug interaction study between the HIV‐1 maturation inhibitor GSK3640254 and a metabolic probe cocktail in healthy participants

Rational formulation engineering of fraxinellone utilizing 6-O-α-D-maltosyl-β-cyclodextrin for enhanced oral bioavailability and hepatic fibrosis therapy

Effects of a Fixed-Dose Co-Formulation of Daclatasvir, Asunaprevir, and Beclabuvir on the Pharmacokinetics of a Cocktail of Cytochrome P450 and Drug Transporter Substrates in Healthy Subjects

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