Strategies and Recommendations for Using a Data-Driven and Risk-Based Approach in the Selection of First-in-Human Starting Dose: An International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Assessment.

Various approaches to first-in-human (FIH) starting dose selection for new molecular entities (NMEs) are designed to minimize risk to trial subjects. One approach uses the minimum anticipated biological effect level (MABEL), which is a conservative method intended to maximize subject safety and designed primarily for NMEs having high perceived safety risks. However, there is concern that the MABEL approach is being inappropriately used for lower risk molecules with negative impacts on drug development and time to patient access. In addition, ambiguity exists in how MABEL is defined and the methods used to determine it. The International Consortium for Innovation and Quality in Pharmaceutical Development convened a working group to understand current use of MABEL and its impact on FIH starting dose selection, and to make recommendations for FIH dose selection going forward. An industry-wide survey suggested the achieved or estimated maximum tolerated dose, efficacious dose, or recommended phase II dose was > 100-fold higher than the MABEL-based starting dose for approximately one third of NMEs, including trials in patients. A decision tree and key risk factor table were developed to provide a consistent, data driven-based, and risk-based approach for selecting FIH starting doses.

Distribution of topical ocular nepafenac and its active metabolite amfenac to the posterior segment of the eye.

Nepafenac ophthalmic suspensions, 0.1% (NEVANAC(®)) and 0.3% (ILEVRO™), are topical nonsteroidal anti-inflammatory drug (NSAID) products approved in the United States, Europe and various other countries to treat pain and inflammation associated with cataract surgery. NEVANAC is also approved in Europe for the reduction in the risk of postoperative macular edema (ME) associated with cataract surgery in diabetic patients. The efficacy against ME suggests that topical administration leads to distribution of nepafenac or its active metabolite amfenac to the posterior segment of the eye. This article evaluates the ocular distribution of nepafenac and amfenac and the extent of local delivery to the posterior segment of the eye, following topical ocular instillation in animal models. Nepafenac ophthalmic suspension was instilled unilaterally in New Zealand White rabbits as either a single dose (0.1%; one drop) or as multiple doses (0.3%, one drop, once-daily for 4 days, or 0.1% one drop, three-times daily for 3 days and one morning dose on day 4). Nepafenac (0.3%) was also instilled unilaterally in cynomolgus monkeys as multiple doses (one drop, three-times daily for 7 days). Nepafenac and amfenac concentrations in harvested ocular tissues were measured using high-performance liquid chromatography/mass spectrometry. Locally-distributed compound concentrations were determined as the difference in levels between dosed and undosed eyes. In single-dosed rabbit eyes, peak concentrations of locally-distributed nepafenac and amfenac showed a trend of sclera > choroid > retina. Nepafenac peak levels in sub-samples posterior to the eye equator and inclusive of the posterior pole (E-PP) were 55.1, 4.03 and 2.72 nM, respectively, at 0.25 or 0.50 h, with corresponding amfenac peak levels of 41.9, 3.10 and 0.705 nM at 1 or 4 h. By comparison, peak levels in sclera, choroid and retina sub-samples in a band between the ora serrata and the equator (OS-E) were 13- to 40-fold (nepafenac) or 11- to 23-fold (amfenac) higher, indicating an anterior-to-posterior directional concentration gradient. In multiple-dosed rabbit eyes, with 0.3% nepafenac instilled once-daily or 0.1% nepafenac instilled three-times daily, cumulative 24-h locally-distributed levels of nepafenac in E-PP retina were similar between these groups, whereas exposure to amfenac once-daily dosing nepafenac 0.3% was 51% of that achieved with three-times daily dosing of 0.1%. In single-dosed monkey eyes, concentration gradients showed similar directionality as observed in rabbit eyes. Peak concentrations of locally-distributed nepafenac were 1580, 386, 292 and 13.8 nM in E-PP sclera, choroid and retina, vitreous humor, respectively, at 1 or 2 h after drug instillation. Corresponding amfenac concentrations were 21.3, 11.8, 2.58 and 2.82 nM, observed 1 or 2 h post-instillation. The data indicate that topically administered nepafenac and its metabolite amfenac reach pharmacologically relevant concentrations in the posterior eye segment (choroid and retina) via local distribution, following an anterior-to-posterior concentration gradient. The proposed pathway involves a choroidal/suprachoroidal or periocular route, along with an inward movement of drug through the sclera, choroid and retina, with negligible vitreal compartment involvement. Sustained high nepafenac concentrations in posterior segment tissues may be a reservoir for hydrolysis to amfenac.

Current Approaches for Absorption, Distribution, Metabolism, and Excretion Characterization of Antibody-Drug Conjugates: An Industry White Paper.

An antibody-drug conjugate (ADC) is a unique therapeutic modality composed of a highly potent drug molecule conjugated to a monoclonal antibody. As the number of ADCs in various stages of nonclinical and clinical development has been increasing, pharmaceutical companies have been exploring diverse approaches to understanding the disposition of ADCs. To identify the key absorption, distribution, metabolism, and excretion (ADME) issues worth examining when developing an ADC and to find optimal scientifically based approaches to evaluate ADC ADME, the International Consortium for Innovation and Quality in Pharmaceutical Development launched an ADC ADME working group in early 2014. This white paper contains observations from the working group and provides an initial framework on issues and approaches to consider when evaluating the ADME of ADCs.

Role of organic cation transporters in dopamine uptake across olfactory and nasal respiratory tissues.

Dopamine has poor oral bioavailability and low permeability across the blood-brain barrier, and yet it has been reported to have good systemic and central nervous system (CNS) bioavailability following nasal administration. The aim of this study was to investigate the extent to which dopamine transport in the olfactory and respiratory mucosae results from the activity of organic cation transporters (OCTs) present in the nasal cavity. Transport studies were carried out to determine the mechanism of dopamine transport across bovine olfactory and nasal respiratory mucosa. Western blotting and immunohistochemistry were performed to determine the expression and localization of organic cation transporter-2, a major transporter of dopamine, in the nasal mucosa. Dopamine transport was found to be saturable across both tissues. Amantadine, an organic cation transporter-1 (OCT-1) and organic cation transporter-2 (OCT-2) mixed inhibitor, decreased dopamine flux to a greater extent than guanidine, a more specific organic cation transporter-2 inhibitor. Immunohistochemistry results showed that organic cation transporter-2 was localized in both the epithelial and submucosal regions of the nasal olfactory and respiratory mucosa. Dopamine transport across the olfactory and respiratory mucosae is partially mediated by organic cation transporters, including OCT-1 and OCT-2. Utilization of uptake transporters may provide the opportunity for improved systemic absorption and targeted CNS delivery of dopamine and other drug compounds following nasal administration.

Metabolism of dopamine by the nasal mucosa.

The nasal route of administration offers several advantages over oral and intravenous administration, including the ability to avoid hepatic first pass metabolism. Dopamine deficiency has been associated with several neurological disorders; it has been shown to have good systemic bioavailability and significant uptake into the CNS following intranasal administration. The purpose of these studies was to investigate the limiting role of mucosal metabolism of dopamine during nasal absorption. In vitro transport and initial rate studies were carried out using nasal mucosal explants to study dopamine permeability and metabolism. Dihydroxyphenylacetic acid (DOPAC) was the only metabolite detected. Monoamine oxidase (MAO), the enzyme responsible for DOPAC formation, was localized to the submucosal region of the nasal explants. The amount of DOPAC formed during the transport studies was less than 0.5% of the initial amount of dopamine placed into the system. Iproniazid, an MAO inhibitor, blocked DOPAC formation but had no effect on dopamine transport. The limited extent of dopamine metabolism compared to its mucosal transport demonstrates that nasal dopamine transport is not significantly reduced by mucosal metabolism and suggests that the nasal route may be promising for the efficient delivery of dopamine to the CNS.

Role of dopamine transporter (DAT) in dopamine transport across the nasal mucosa.

Dopamine is a catecholamine neurotransmitter necessary for motor functions. Its deficiency has been observed in several neurological disorders, but replacement of endogenous dopamine via oral or parenteral delivery is limited by poor absorption, rapid metabolism and the inability of dopamine to cross the blood-brain barrier. The intranasal administration of dopamine, however, has resulted in improved central nervous system (CNS) bioavailability compared to that obtained following intravenous delivery. Portions of the nasal mucosa are innervated by olfactory neurons expressing dopamine transporter (DAT) which is responsible for the uptake of dopamine within the central nervous system. The objective of these studies was to study the role of DAT in dopamine transport across the bovine olfactory and nasal respiratory mucosa. Western blotting studies demonstrated the expression of DAT and immunohistochemistry revealed its epithelial and submucosal localization within the nasal mucosa. Bidirectional transport studies over a 0.1-1 mM dopamine concentration range were carried out in the mucosal-submucosal and submucosal-mucosal directions to quantify DAT activity, and additional transport studies investigating the ability of GBR 12909, a DAT inhibitor, to decrease dopamine transport were conducted. Dopamine transport in the mucosal-submucosal direction was saturable and was decreased in the presence of GBR 12909. These studies demonstrate the activity of DAT in the nasal mucosa and provide evidence that DAT-mediated dopamine uptake plays a role in the absorption and distribution of dopamine following intranasal administration.

Comparison of human tracheal/bronchial epithelial cell culture and bovine nasal respiratory explants for nasal drug transport studies.

Ten drug compounds with varying physicochemical properties and transporter substrate specificities were investigated to compare their in vitro permeabilities across bovine nasal respiratory explants and the EpiAirway system, both established models for the assessment of nasal drug absorption. Permeability across the bovine explants and EpiAirway correlated well with the partitioning behavior of compounds whose clogDC values were greater than 0. The permeabilities of all ten compounds were well-correlated between the two tissue models, with the permeability values through the EpiAirway tissues being approximately 10-fold higher than through the bovine explants due to the thickness differences between the models. For more lipophilic compounds, the in vitro permeabilities measured with both tissue systems were also predictive of the reported in vivo nasal bioavailabilities. Deviations from these correlations were observed for compounds reported to be substrates of p-glycoprotein or OCT transporters, and differences were also seen between the permeabilities measured in the tissue models for these compounds. Both models can be used to estimate the systemic bioavailability of moderately lipophilic compounds administered intranasally, while each may have particular advantages or disadvantages in estimating the bioavailability of drug compounds that are subject to local mucosal metabolism or to carrier-mediated uptake or efflux.