Systemic Bioavailability of Sublingual Atropine Ophthalmic Solution: a Phase I Study in Healthy Volunteers with Implications for Use as a Contingency Medical Countermeasure.

INTRODUCTION: Atropine sulfate is an FDA-approved medical countermeasure (MCM) for the treatment of organophosphorus nerve agent and organophosphate pesticide toxicity. Sufficient MCM supplies must be available in an incident involving a mass human exposure either from an accidental chemical release or a terrorist attack. METHODS: We performed a randomized, 3-sequence, 3-period phase I crossover study to assess the bioavailability and pharmacokinetics (PK) of a single dose (0.5 mg and 1.0 mg) of 1% ophthalmic atropine sulfate solution administered sublingually to 15 healthy adult volunteers. The primary endpoint was evaluation of the bioavailability of each of the two sublingual doses against a 1.0 mg reference intravenous (IV) atropine dose. Secondary endpoints included the safety and tolerability (xerostomia scale) of atropine sulfate administered sublingually. RESULTS: Sublingual atropine was safe (no severe AEs or SAEs were reported with either dose) and well tolerated, with a single subject reaching maximum xerostomia on a single dosing day. The geometric mean AUC∞ was 286.40, 493.81, and 816.47 min*ng/mL for the 0.5 mg and 1.0 mg sublingual doses, and the 1.0 mg IV dose, respectively. Compared to IV administration, the 1.0 mg sublingual dose produced 0.60 (90% CI: 0.55-0.66) of the overall concentration of atropine over time (AUC∞). CONCLUSION: Sublingual atropine sulfate 1% ophthalmic solution may be an alternative formulation and route of administration combination which expands the capacity and dosing options of atropine as a nerve agent MCM.

Improved Bioavailability with Dry Powder Cannabidiol Inhalation: A Phase 1 Clinical Study.

Oral cannabidiol (CBD) is approved by the Food and Drug Administration (FDA) to treat patients with Dravet and Lennox-Gastaut syndromes and tuberous sclerosis complex. The therapeutic potential of oral CBD formulations is limited by extensive first-pass hepatic metabolism. Following oral administration, the inactive metabolite blood concentration is ∼40-fold higher than CBD. Inhalation bypasses the pharmacokinetic (PK) variability attributed to irregular gastrointestinal absorption and first-pass hepatic metabolism and may efficiently deliver CBD into systemic circulation. This phase 1 study compared the PK of a dry-powder inhaler (DPI) CBD formulation (10 mg powder containing 2.1 mg CBD) with an oral CBD solution (Epidiolex®, 50 mg) in healthy participants. Following a single dose of Epidiolex or DPI CBD (n=10 PK evaluable participants each), the maximum CBD concentration for the inhaled powder was 71-fold higher than that of Epidiolex while administering 24-fold less CBD. The mean time to reach maximum concentration was 3.8 min for the DPI CBD formulation compared with 122 min for Epidiolex. Both Epidiolex and DPI CBD were generally safe and well-tolerated. These data indicate that DPI CBD provided more rapid onset and increased bioavailability than oral CBD and support further investigations on the use of DPI CBD for acute indications.

Pharmacokinetics of imiquimod 3.75% cream applied daily for 3 weeks to actinic keratoses on the face and/or balding scalp.

Imiquimod 3.75% cream is a topical formulation of imiquimod intended for daily application to treat actinic keratoses of the entire face or balding scalp. The objective of the study was to characterize serum imiquimod and metabolite pharmacokinetics. Nineteen subjects with actinic keratoses applied two packets of imiquimod 3.75% cream (18.75 mg imiquimod total) once daily for 21 days to a treatment area approximately 200 cm(2) in size on the face and/or balding scalp. Blood samples were obtained prior to application of doses 1, 7, 14 and 21, and at selected timepoints after application of doses 1 and 21. After multiple dosing (day 21) serum imiquimod mean C (max) was 0.323 (standard deviation 0.159) ng/mL, mean AUC(0-24) 5.974 (3.088) ng h/mL, and mean T(1/2) 29.3 (17.0) h. Steady-state was achieved by day 14; multiple dose accumulation ratios were 2.8 based on imiquimod C (max) and 3.9 based on AUC. Serum concentrations of imiquimod metabolites were only sporadically quantifiable in three subjects. One subject discontinued from study for adverse events of body aches and fatigue that were attributed to study drug. Treatment-related adverse events occurred in 42.1% (8/19) of the subjects. Systemic imiquimod exposure, as reflected by serum drug concentration, was low after daily application of two packets of imiquimod 3.75% cream for 21 days. Steady state was achieved by day 14, and the observed half-life of approximately 29 h supports daily dosing of the product.