Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose

Contrera, Joseph F.; Matthews, Edwin J.; Kruhlak, Naomi L.; Benz, R.

doi:10.1016/j.yrtph.2004.08.004

Cited by 82 publications

(64 citation statements)

References 15 publications

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“…For mice in the rimonabant group, rimonabant was mixed with baked high cholesterol chow at a final concentration of 0.065% 16) and provided every day for 3 months. According to the Food and Drug Administration-recommended formula, this animal dose of 8 mg/kg/day is equal to a human dose of 0.33 mg/kg/day 17) . Twenty-four mice (12 controls and 12 receiving 8 mg/kg/day) were used for in vivo evaluation.…”

Section: Protocolmentioning

confidence: 99%

Cannabinoid 1 Receptor Blockade Reduces Atherosclerosis with Enhances Reverse Cholesterol Transport

Sugamura

Sugiyama

Fujiwara

et al. 2010

JAT

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Aim: A recent clinical study using coronary intravascular ultrasound showed that rimonabant, a cannabinoid 1 (CB1) receptor antagonist, significantly reduced total atheroma volume, suggesting that CB1 receptor blockade could be beneficial in anti-atherogenic therapy. The reverse cholesterol transport (RCT) system plays important roles in atherogenesis. We investigated whether CB1 receptor blockade could modulate atherogenesis in mice. Methods and Results: Oral administration of rimonabant (8 mg/kg/day) to apolipoprotein E-deficient mice for 3 months significantly reduced the relative area of atherosclerotic lesions in the aorta (vehicle; 12.6 4.0% vs. rimonabant; 9.7 2.3, n 12 each, p 0.05) with an increase in serum adiponectin levels (15.6 2.3 g/mL vs. 12.2 2.1, n 12 each, p 0.001), without affecting body weight or serum cholesterol levels. Rimonabant tended to increase serum high-density lipoprotein cholesterol (HDL-C) (p 0.05). The relative area of atherosclerotic lesions in the aorta correlated inversely with serum HDL-C levels (r 0.45, n 24, p 0.05). Rimonabant upregulated the mRNA expression levels of various components of the RCT system on THP-1 cell-derived macrophages (scavenger receptor B1: 1.15 0.12 fold, n 6; p 0.05, ATP-binding cassette [ABC] transporter G1: 1.23 0.11 fold, n 6; p 0.01), but not ABCA1 (1.13 0.20 fold, n 6; p 0.13). Conclusion: CB1 receptor blockade reduced atherosclerosis in apoE-deficient mice through an increase in serum adiponectin levels and activation of the RCT system. CB1 receptor blockade may be therapeutically beneficial for atherogenesis by increasing the serum adiponectin level and enhancing of the RCT system.

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Section: Protocolmentioning

confidence: 99%

Cannabinoid 1 Receptor Blockade Reduces Atherosclerosis with Enhances Reverse Cholesterol Transport

Sugamura

Sugiyama

Fujiwara

et al. 2010

JAT

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“…It is essentially equivalent to the NOAEL in humans, a dose beyond which adverse (toxicological) or undesirable pharmacological effects are observed. It has been considered that with the exception of chemotherapeutics and immunosuppressants, the MRTD/10 would correspond to a dose exerting neither therapeutic nor chronic adverse effects in humans Contrera et al, 2004). For nonpharmaceutical chemicals, there is no desired pharmacological effect and any compound-related effect could be interpreted as adverse or non-desirable effect.…”

Section: How Is (Q)sar Analysis Used In Your Organisation?mentioning

confidence: 99%

Applicability of QSAR analysis to the evaluation of the toxicological relevance of metabolites and degradates of pesticide active substances for dietary risk assessment

2010

EFSA Supporting Publications

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“…The MABEL is the lowest dose that is associated with any biological effect, whether it be toxicity or a desired pharmacological effect (16). MABEL is calculated using the following PK/PD data: (1) in vitro target binding and receptor occupancy in target human and animal cells, (2) in vitro concentration-response curves in target human and animal cells, (3) in vivo dose-exposure-response profiles in relevant animal species, and (4) exposures at pharmacological active doses in relevant animal species. To minimize the potential risks of adverse effects in humans, a safety factor is applied in the calculation of the FIH dose from the MABEL.…”

Section: Mabel-based Approachmentioning

confidence: 99%

“…The starting dose must be low enough to be safe but high enough to avoid excessive dose escalations, which are costly and timeconsuming. The most widely used method for FIH dose estimation is based on no observable adverse effect levels (NOAELs) in multiple species (1,2). NOAELs are determined in relevant animal studies and normalized to body surface area (in milligrams per square meter), and then extrapolated to human equivalent doses (HEDs).…”

Section: Introductionmentioning

confidence: 99%

Applications of Human Pharmacokinetic Prediction in First-in-Human Dose Estimation

Zou

Zheng

et al. 2012

AAPS J

113

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Abstract. Quantitative estimations of first-in-human (FIH) doses are critical for phase I clinical trials in drug development. Human pharmacokinetic (PK) prediction methods have been developed to project the human clearance (CL) and bioavailability with reasonable accuracy, which facilitates estimation of a safe yet efficacious FIH dose. However, the FIH dose estimation is still very challenging and complex. The aim of this article is to review the common approaches for FIH dose estimation with an emphasis on PK-guided estimation. We discuss 5 methods for FIH dose estimation, 17 approaches for the prediction of human CL, 6 methods for the prediction of bioavailability, and 3 tools for the prediction of PK profiles. This review may serve as a practical protocol for PK-or pharmacokinetic/pharmacodynamic-guided estimation of the FIH dose.

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Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose

Cited by 82 publications

References 15 publications

Cannabinoid 1 Receptor Blockade Reduces Atherosclerosis with Enhances Reverse Cholesterol Transport

Cannabinoid 1 Receptor Blockade Reduces Atherosclerosis with Enhances Reverse Cholesterol Transport

Applicability of QSAR analysis to the evaluation of the toxicological relevance of metabolites and degradates of pesticide active substances for dietary risk assessment

Applications of Human Pharmacokinetic Prediction in First-in-Human Dose Estimation

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