Variability of Skin Pharmacokinetic Data: Insights from a Topical Bioequivalence Study Using Dermal Open Flow Microperfusion

Bodenlenz, Manfred; Augustin, Thomas; Birngruber, Thomas; Tiffner, Katrin I.; Boulgaropoulos, Beate; Schwingenschuh, Simon; Raney, Sam G.; Rantou, Elena; Sinner, Frank

doi:10.1007/s11095-020-02920-x

Cited by 17 publications

(11 citation statements)

References 35 publications

(64 reference statements)

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“…In addition, the skin has high inter-and intraindividual variability that may depend on various physiological factors including skin color, age, sex, and anatomical location [3]. Any of these variables, individually or in combination, may influence the skin permeability or barrier properties [4]. All commercially available transdermal patches are approved for application only at specific body sites because of the variation in drug absorption that can occur from application to other locations on the body [5,6].…”

Section: Introductionmentioning

confidence: 99%

Micropore Closure Rates following Microneedle Application at Various Anatomical Sites in Healthy Human Subjects

Ogunjimi

Lawson

Carr

et al. 2021

Skin Pharmacol Physiol

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Introduction: The continuous availability of open micropores is crucial for a successful microneedle (MN) drug delivery strategy. However, micropore lifetime depends on intrinsic skin functional and anatomical characteristics, which vary significantly at different anatomical sites. Objective: This pilot study explored if differences exist in micropore closure timeframes at 3 anatomical sites – upper arm, volar forearm, and abdomen. Methods: Healthy subjects (n = 35) self-identifying as Asian (n = 9), Bi-/multiracial (n = 2), Black (n = 9), Latino (n = 6), and White (n = 9) completed the study. The upper arm, volar forearm, and abdomen were treated with MNs; skin impedance and transepidermal water loss (TEWL) were measured at baseline and post-MN to confirm micropore formation. Impedance was measured for 3 days to evaluate micropore lifetime. Measurements of L*, which quantifies the skin lightness/darkness, were made using a tristimulus colorimeter. Micropore lifetime was determined by comparing baseline and post-MN impedance measurements, and micropore closure half-life was predicted using mathematical modeling. Results: Post-MN increase in TEWL and decrease in impedance were significant (p < 0.05), confirming successful micropore formation at all anatomical sites. When data were analyzed according to subject self-identified racial/ethnic groups, the mean micropore closure time at the abdomen (63.09 ± 13.13 h) was longer than the upper arm (60.34 ± 14.69 h) and volar forearm (58.29 ± 16.76 h). The predicted micropore closure half-life at anatomical sites was the abdomen (25.86 ± 14.96 h) ≈ upper arm (23.69 ± 13.67 h) > volar forearm (20.2 ± 11.99 h). Differences were not statistically significant between groups. Objective categorization by L* showed that the darker skin may be associated with longer micropore closure time at the abdomen site. Conclusions: Our results suggest that anatomical site of application may not be a source of significant variability in micropore closure time. These findings may help reduce the number of physiological parameters that need to be explicitly considered when developing drug products to support MN-assisted drug delivery strategies.

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Section: Introductionmentioning

confidence: 99%

Micropore Closure Rates following Microneedle Application at Various Anatomical Sites in Healthy Human Subjects

Ogunjimi

Lawson

Carr

et al. 2021

Skin Pharmacol Physiol

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“…In the main clinical dOFM BE study, the generic test product and the reference product are tested in parallel by applying them on adjacent application sites in the same healthy participant. This design reduces inter-subject variability and thus lowers the number of participants needed for clinical PK-based dOFM studies relative to clinical endpoint studies ( Bodenlenz et al, 2020 ). A high level of standardization in each study is necessary irrespective of the tested drug products.…”

Section: Clinical Pk-based Dofm Studiesmentioning

confidence: 99%

“…In addition, dOFM studies have also shown a low intra-subject variability (9%–18% log AUC) ( Bodenlenz et al, 2020 ) indicating reproducibility due to high methodological standardization. All dOFM material and study procedures have been thoroughly optimized and highly standardized in the last few years which includes the use of template frames for probe placement, skin pre-cooling procedures, probe depths monitoring (by ultrasound), room temperature and humidity control, skin care before the study, implantation procedure, and substance application procedure, all of which led to high‐quality data that enable successful BE assessment.…”

Section: Strengths Of Dofm For Pk-based Be Studiesmentioning

confidence: 99%

Dermal open flow microperfusion for PK-based clinical bioequivalence studies of topical drug products

et al. 2022

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Topically applied drug products have experienced an extraordinary price increase in the United States, mostly due to a lack of generic products. Generic drug development is hindered by high costs and risks associated with clinical endpoint studies required to show bioequivalence (BE) of prospective generic products relative to their reference products. There is a continued need for cost- and time-efficient alternatives to clinical endpoint studies to determine BE of topically applied dermal drug products. Cutaneous PK-based BE studies present such an alternative and dOFM (dermal open flow microperfusion) has already been successfully used in several verifications studies to show an accurate and sensitive assessment of the rate and extent at which drugs become available in the skin. dOFM technology is discussed as well as the dOFM setup of clinical pilot and main studies to achieve BE assessment with a minimum number of participants and an outlook is given on the use of dOFM technology for other drug products.

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“…Human and/or minipig concentrations of various drugs in the dermis or epidermis assessed by methods such as OFM, mass spectroscopy imaging, and LCM have illustrated that drug concentrations in viable skin are a fraction of that found in the SC. In humans, for example, studies with OFM have measured average dermal concentrations of an antiviral (acyclovir) and phosphodiesterase inhibitor (LEO 29102) ranging from ~10 to 1000 nM when applied topically (Bodenlenz et al, 2020;Eirefelt et al, 2020). Likewise, in a pig OFM study, dermal interstitial fluid concentrations of the Janus kinase inhibitors tofacitinib and LEO 27319A were measured at ≤ 100 nM (Handler et al, 2021).…”

Section: Drug Concentrations In Skinmentioning

confidence: 99%

Development challenges for carcinogenicity risk assessments of topical drugs

et al. 2022

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The nonclinical safety package to support development and approval of drugs intended to be administered by topical application generally follows International Council for Harmonisation multidisciplinary 3 (ICH M3) and topic specific safety (ICH S) guidances. However, some aspects of topical drug development may require case-by-case determination of nonclinical safety strategies. The necessity to conduct a dermal rodent carcinogenicity study is one such example that is not considered an obligate component of a nonclinical safety data package for drug approval. While absence of systemic exposure, as stated in ICH M3, is a primary reason to forego a dermal carcinogenicity assessment, there may also be other factors for consideration in determining the need for a life-time carcinogencity study by dermal route to aid in the overall human cancer risk assessment. We therefore reviewed nonclinical carcinogencity data packages from drugs approved by the FDA or PMDA over a ~25 year time period to evaluate outcomes of oral versus topical carcinogencity studies and to understand their utility for informing the overall human risk assessment. We also discuss various other properties of topical small molecules that could impact the decisions to conduct a dermal life-time rodent carcinogenicity study. Collectively, the need to conduct 2-year dermal carcinogenicity studies in rodents should be determined case-by-case and consider scientific factors such existing systemic toxicity and carcinogenicity study data, anticipated drug exposures in skin, skin evaluation from the chronic minipig toxicity study, and genetic toxicity profile.

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Variability of Skin Pharmacokinetic Data: Insights from a Topical Bioequivalence Study Using Dermal Open Flow Microperfusion

Cited by 17 publications

References 35 publications

Micropore Closure Rates following Microneedle Application at Various Anatomical Sites in Healthy Human Subjects

Micropore Closure Rates following Microneedle Application at Various Anatomical Sites in Healthy Human Subjects

Dermal open flow microperfusion for PK-based clinical bioequivalence studies of topical drug products

Development challenges for carcinogenicity risk assessments of topical drugs

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