Prediction of human percutaneous absorption from in vitro and in vivo animal experiments

Yoshimatsu, Hiromichi; Ishii, Kunikazu; Konno, Yasuhiko; Satsukawa, Masahiro; Yamashita, Shinji

doi:10.1016/j.ijpharm.2017.10.048

Cited by 15 publications

(8 citation statements)

References 22 publications

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“…Human skin remains the ‘gold‐standard’ to evaluate the skin delivery of chemicals for transdermal and topical purposes researchers . However, porcine skin, whilst not a perfect model to predict human skin permeation is a suitable model to assess PR mammalian skin permeation before progressing to studies in human skin .…”

Section: Resultsmentioning

confidence: 99%

Characterization and topical delivery of phenylethyl resorcinol

Zhang¹,

Sil

Kung³

et al. 2019

Intern J of Cosmetic Sci

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Objective Phenylethyl resorcinol (PR) has been used widely in the personal care industry as a novel skin lightening ingredient. Surprisingly, there is only limited information describing the physicochemical properties of this active. Therefore, the primary objective of this study was to perform a comprehensive characterization of PR. A secondary objective was to investigate the delivery of this molecule to mammalian skin. Methods Phenylethyl resorcinol was characterized using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and nuclear magnetic resonance (NMR). A new high‐performance liquid chromatographic (HPLC) method for analysis of PR was developed and validated. The log P (octanol water partition coefficient), value, solubility and short‐term stability of PR in a series of vehicles were also determined using HPLC. The evaporation of the selected vehicles was examined using dynamic vapour sorption (DVS). The permeation profiles of PR were investigated under finite dose conditions in porcine and human skin. Results The melting point of PR was determined to be 79.13 °C and the measured log P (octanol water partition coefficient) at 21 °C was 3.35 ± 0.03. The linearity of the HPLC analytical method was confirmed with an r2 value of 0.99. Accuracy of the method was evaluated by average recovery rates at three tested concentrations, and the values ranged from 99 to 106%. The limit of detection (LOD) and limit of quantification (LOQ) were 0.19 and 0.57 μg mL−1, respectively. The solubility of PR in PG, DMI, glycerol was within the range of 367 to 877 mg mL−1. The stability of PR in tested solvents was also confirmed by the 72 h stability studies. From the DVS studies, 70–125% of applied formulations were recovered at 24 h. The permeation through porcine skin at 24 h ranged from 4 to 13 μg cm−2, while the corresponding amounts of PR delivered through human skin were 2 to 10 μg cm−2. Conclusion The physicochemical properties of PR confirm it is suitable for dermal delivery. In this study, propylene glycol was the most promising vehicle for PR delivery to human skin. Future work will expand the range of vehicles studied and explore the percutaneous absorption from more complex formulations.

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Section: Resultsmentioning

confidence: 99%

Characterization and topical delivery of phenylethyl resorcinol

Zhang¹,

Sil

Kung³

et al. 2019

Intern J of Cosmetic Sci

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“…However, this was not available at the time and future availability was unclear. We therefore turned to a plausible alternative that appeared to have good permeability in preclinical testing, both in vitro experiments using human skin, 33 and using animal models that have been shown to be predictive of permeation through human skin (nude rat and minipig) 8,34,35 . Thus, the poor permeation of the modified transdermal formulation tested in our trial was surprising, and points to the need for planned interim analyses and Bayesian adaptive design in trials of novel agents to confirm permeation even when preclinical data are encouraging.…”

Section: Discussionmentioning

confidence: 94%

Local Transdermal Delivery of Telapristone Acetate Through Breast Skin, Compared With Oral Treatment: A Randomized Double‐Blind, Placebo‐Controlled Phase II Trial

Lee

Pilewskie

Karlan

et al. 2020

Clin Pharma and Therapeutics

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Oral breast cancer prevention medications entail systemic exposure, limiting acceptance by high‐risk women. Delivery through the breast skin, although an attractive alternative, requires demonstration of drug distribution throughout the breast. We conducted a randomized double‐blind, placebo‐controlled phase II clinical trial comparing telapristone acetate, a progesterone receptor antagonist, administered orally (12 mg/day) or transdermally (12 mg/breast) for 4 ± 1 weeks to women planning mastectomy. Plasma and tissue concentrations, measured at five locations in the mastectomy specimen using liquid chromatography tandem mass spectrometry were compared. In 60 evaluable subjects, median drug concentration (ng/g tissue) was 103 (interquartile range (IQR): 46.3–336) in the oral vs. 2.82 (IQR: 1.4–5.5) in the transdermal group. Despite poor dermal permeation, within‐breast drug distribution pattern was identical in both groups (R2 = 0.88, P = 0.006), demonstrating that transdermally and orally delivered drug is distributed similarly through the breast, and is strongly influenced by tissue adiposity (P < 0.0001). Other skin‐penetrant drugs should be tested for breast cancer prevention.

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“…As we noted above, "The minipig is the species of choice to investigate dermal absorption in preclinical drug development" (Preube and Skaanild, 2012). The intent of this brief review of dermal absorption is to focus on several publications that have evaluated transdermal drug absorption comparing in vitro and in vivo data in the pig (Yamamoto et al, 2017;Yoshimatsu et al, 2017). We also provide in-house data generated at Guangzhou Dazhou Biomedicines (unpublished data) to illustrate the development of an IVIVC to demonstrate the utility of this approach.…”

Section: Dermal Absorptionmentioning

confidence: 99%

“…and generally agreed upon, and the in vitro data are found to have adequate correlation to in vivo results, then human skin studies need not be done, that is, prediction of human PK directly based on in vitro pig permeability, as demonstrated by Yamamoto et al (2017). Yoshimatsu et al (2017) conducted in vitro and in vivo studies on six drugs (ketoprofen, flurbiprofen, diclofenac, buprenorphine, fentanyl, and lidocaine) in mice, rats, minipigs, and humans [diclofenac and lidocaine data from the Yamamoto et al 2017study]. The study protocols were basically the same as in Yamamoto et al (2017).…”

Section: Dermal Absorptionmentioning

confidence: 99%

Porcine Prediction of Pharmacokinetic Parameters in People: A Pig in a Poke?

Tang

Mayersohn

2018

Drug Metab Dispos

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The minipig has become an animal of considerable interest in preclinical drug development. It has been used in toxicology research and in examining/establishing regulatory guidelines as a nonrodent animal model. We have reviewed some basic issues that one would want to consider in the development and testing of any animal model for humans. The pig is a reasonable alternative to the dog, but there are some clear limitations and unexplained disparities in the literature, which require further study; primary among these is the need for standardization in choice of breed and sex and routine protocols. The minipig offers numerous advantages over other established animal models, and it has similarities to the human with regard to anatomy, physiology, and biochemistry. The gastrointestinal tract is structurally and functionally similar to humans. This appears to be true for enzymes and transporters in the gut as well, but more study is needed. One major concern is assessment of oral drug absorption, especially with regard to potential food effects due to gastric emptying differences, yet this does not appear to be a consistent observation. Hepatic metabolism seems to reflect enzymatic patterns in humans, with some differences. Kidney function seems similar to humans but requires further study. We have analyzed literature data that suggest the pig would offer a reasonable model for human oral bioavailability and for allometric predictions of clearance. The minipig appears to be the model for dermal absorption in humans, and we discuss this in terms of literature data and our own in-house experience.

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Prediction of human percutaneous absorption from in vitro and in vivo animal experiments

Cited by 15 publications

References 22 publications

Characterization and topical delivery of phenylethyl resorcinol

Characterization and topical delivery of phenylethyl resorcinol

Local Transdermal Delivery of Telapristone Acetate Through Breast Skin, Compared With Oral Treatment: A Randomized Double‐Blind, Placebo‐Controlled Phase II Trial

Porcine Prediction of Pharmacokinetic Parameters in People: A Pig in a Poke?

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