ABSTRACT:In humans, indirect evidence suggests that hypoxia reduces the rate of biotransformation of drugs cleared by cytochrome P450 (P450) subfamilies CYP1A, 2B, and 2C. The aim of this study was to assess whether acute moderate hypoxia modulates the expression of CYP2B4, 2C5, and 2C16 in vivo, and to determine whether the changes in hepatic P450 are conveyed by serum mediators. Moreover, because hypoxia increases the expression of P-glycoprotein in vitro, we examined whether in vivo acute moderate hypoxia modulates the expression of several membrane transporters in the liver. Rabbits and rats were exposed to a fractional concentration of oxygen of 8% for 48 h to generate a stable arterial partial pressure of O 2 of 34 ؎ 1 mm Hg. Compared with rabbits breathing room air, hypoxia in rabbits reduced the amount of CYP1A1, 1A2, 2B4, 2C5, and 2C16 proteins and increased the expression of CYP3A6. Sera of rabbits with hypoxia were fractionated by size exclusion chromatography, the fractions were tested for their ability to modify the expression of P450 isoforms, and serum mediators were identified through neutralization experiments. The serum mediators responsible for the downregulation of P450 isoforms were interferon-␥, interleukin-1 (IL-1), and IL-2. In vivo, in rats, hypoxia increased the mRNA and protein expression of P-glycoprotein but did not affect the mRNA of breast cancer resistance protein and organic anion-transporting polypeptide 2. It is concluded that in vivo, hypoxia down-regulates rabbit hepatic CYP1A1, 1A2, 2B4, 2C5, and 2C16 and up-regulates CYP3A6. CYP3A11 and P-glycoprotein were up-regulated in the livers of hypoxic rats.In patients with cardiorespiratory diseases, acute hypoxemia appears to reduce the ability of cytochrome P450 isoforms to catalyze the biotransformation of xenobiotics. Patients with pulmonary insufficiency who show an impairment of their general state present an increased incidence of adverse effects, e.g., grand mal seizures, associated with the administration of "usual" doses of theophylline. Theophylline clearance is significantly reduced in patients with acute cardiogenic pulmonary edema (Piafsky et al., 1977) and in patients with worsening airway obstruction, severe bronchial obstruction, congestive heart failure, and pneumonia (Vozeh et al., 1978).In humans, at therapeutic concentrations, the biotransformation of theophylline is primarily catalyzed by CYP1A2, whereas CYP2D6, 2E1, and 3A4 exhibit low affinity and variable capacity (Ha et al., 1995). Rabbits exposed to a fractional concentration of inspired O 2 (FiO 2 ) of 10% for 24 h demonstrate a reduced clearance of theophylline and decreased expression of CYP1A1 and 1A2, although the expression of CYP3A6 is increased (Kurdi et al., 1999). In rabbits subjected to acute moderate hypoxia, hepatic down-regulation of CYP1A1 and 1A2 is triggered by serum mediators, e.g., interferon-␥ (IFN-␥), interleukin 2 (IL-2), and IL-1; the up-regulation of CYP3A6 is, at least in part, associated with erythropoietin (Epo) (Fradette et ...
Pharmacokinetic-pharmacodynamic (PK-PD) data analyses from early hepatitis C virus (HCV) clinical trials failed to show a good correlation between the plasma inhibitory quotient (IQ) and antiviral activity of different classes of directly acting antiviral agents (DAAs). The present study explored whether use of the liver partition coefficient-corrected IQ (LCIQ) could improve the PK-PD relationship. Animal liver partition coefficients (Kp liver ) were calculated from liver to plasma exposure ratios. In vitro hepatocyte partition coefficients (Kp hep ) were determined by the ratio of cellular to medium drug concentrations. Human Kp liver was predicted using an in vitro-in vivo proportionality method: the species-averaged animal Kp liver multiplied by the ratio of human Kp hep over those in animals. LCIQ was calculated using the IQ multiplied by the predicted human T he inhibitory quotient (IQ) is a common pharmacological predictor of antiviral activity and generally represents the ratio between the trough plasma concentration (C min ) and an in vitro potency parameter such as 50% effective concentration (EC 50 ) (3). Several modifications have been proposed to improve the prognostic value of the plasma IQ-antiviral response relationship, including the use of serum-shifted EC 50 s, the consideration of intracellular drug concentrations, and the potential complication related to drug resistance mutations (1, 3), as well as the proposed instantaneous IQ model, which suggested that the slope of the dose-response curve is another critical fact to consider (34). Recently, several directly acting antivirals (DAAs) targeting HCV have been advanced into clinical trials, and the first DAAs have now been approved for use in combination therapy with pegylated interferon and ribavirin (2,18,21,32,35). The first DAA tested in chronic hepatitis C virus (HCV)-infected patients with potent antiviral effect was BILN 2061 (16, 20), which showed a clear dosedependent in vivo activity. Even at the low oral twice-daily (b.i.d.) dose of 25 mg, a mean of 2-log 10 IU/ml viral load reduction (VLR) was observed following a brief treatment (2 days) (16). The corresponding mean plasma IQ was 6.6 at this low oral dosage. A similar plasma IQ, but significantly greater antiviral effects, was observed for telaprevir dosed at 750 mg three times a day (t.i.d.), based on published clinical pharmacokinetic (PK) data (33) and the EC 50 s measured under the same experimental condition as used for BILN 2061 from our lab. Clinical trials for the polymerase inhibitor BILB 1941 (11) demonstrated that a mean plasma IQ of 21 was achieved with the t.i.d. oral dose of 300 mg (about 3.5-fold greater than for BILN 2061 at 25 mg b.i.d. or telaprevir at 750 mg t.i.d.). Yet this higher plasma IQ was associated with much lower antiviral effects in the clinic, with a mean viral load reduction of only 1 log 10 IU/ml. Correction of plasma IQ using serum-shifted EC 50 s, or plasma protein binding-corrected IQs, failed to improve the PK-pharmacodynamics (PD) relationshi...
1. The present study evaluates which factors should be incorporated into a simplified approach to reasonably predict CYP3A-mediated drug-drug interaction (DDI) at an early drug discovery stage. 2. CYP3A IC50 values were obtained using human liver microsomes (HLM) and hepatocytes. Plasma and microsomal protein binding and in vitro hepatocyte partition coefficient (Kp) were also determined for 10 drugs. Therapeutic human maximum plasma concentrations (Cmax) were retrieved from the literature. DDI predictions were performed using an equation incorporating the fraction of the substrate metabolized by CYP3A with the total or free plasma Cmax, with or without correction for hepatocyte Kp. 3. Based on the Ki data from HLM, the use of total Cmax provided a prediction of DDI within 2-fold of the observed clinical values for 9 out of 10 drugs. 4. In comparison, free drug corrections for both Cmax and Ki values from HLM led to an underprediction of DDI (>3-fold error for five drugs). 5. Data from hepatocytes showed, in general, lower prediction accuracy than data from HLM. 6. CYP3A-mediated DDIs can be predicted with a high level of accuracy based on Ki estimates from HLM data and the total therapeutic plasma Cmax of the inhibitors. This approach should be widely applicable to the assessment of clinically significant DDIs risk in early drug discovery programs.
ONO-5788 is a novel low molecular weight orally administered molecule with potent and selective agonistic effects at the human SST2 receptor subtype. ONO-5788 could offer the advantages of a more convenient route of administration for patients with acromegaly and other indications and also a preferential safety profile compared to injections. Methods : This First in Human study includes a double-blind, randomized, placebo-controlled, single ascending dose (SAD) part (including an assessment of food effect) in healthy adult male and female volunteers, 18-55 years of age. 34 males and 14 females were enrolled. Subjects were randomised to ONO-5788 or placebo (6:2 ratio) in each cohort with escalating doses of ONO-5788 (0.4, 1.6, 5, 20, 50 or 120mg) assessed. The first 2 dose levels were dosed as an oral liquid solution, the 4 remaining dose levels were dosed as oral API in capsule. Findings : Preliminary blinded data suggested no significant safety issues during administration of single doses of ONO-5788. A low incidence of mild to moderate gastrointestinal adverse events was observed at the higher doses (loose stools n=4; abdominal cramping n=3; abdominal discomfort, abdominal tenderness, discolouration of stools, pale stools, dyspepsia, nausea, all n=2). There were no safety findings for safety labs, ECGs or vital signs and no SAEs were reported. A transient increase in serum glucose was noted at 6 hours post-dose (3 hours post-meal) which followed a dose-response pattern when comparing mean glucose values across all 6 cohorts; all subjects were asymptomatic and no intervention was required. Pharmacokinetics of ONO-5788 and its active metabolite (ONO-ST1-641) were well characterized at the doses tested. Parent drug concentrations were notably higher than the active metabolite (approximately 40-fold greater). A 300-fold dose range was explored (0.4mg to 120mg) but, using arithmetic mean Cmax, AUClast and AUCinf values, ONO-5788 exposure was approximately 59-90 times higher at the highest dose compared to the lowest and ONO-ST1-641 exposure was 139-193 times higher at the highest dose. There were less than dose-proportional increases in exposure observed with both ONO-5788 and ONO-ST1-641 at doses above 20mg. Lower exposure was observed with food at the 20mg dose. The mean half-life of ONO-5788 ranged between 6.4-22 hours and for ONO-ST1-641 between 62-110 hours. Conclusion : ONO-5788 was found to be well tolerated in this SAD study at all doses tested. The pharmacokinetic profiles of ONO-5788 and its active metabolite were well characterised with a half-life suggesting the potential for once-daily dosing. Safety, tolerability, pharmacokinetics and pharmacodynamics will continue to be assessed in healthy volunteers with multiple dosing, dosing of a cohort of elderly subjects and a proof-of-principle study to further characterize ONO-5788 prior to studies in patients.
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