Dose translation between laboratory animals and human in preclinical and clinical phases of drug development.

Preclinical Research & Development Appropriate translation and determination of the maximum recommended starting dose in human is a vital task in new drug development and research. Allometric scaling is the most frequently used approach for dose extrapolation based on normalization of dose-to-body surface area. Misinterpretation of allometric dose conversion and safety factor application can lead to major problems in calculating maximum recommended safe starting dose in first-in-human clinical trials. Therefore, dose translation always necessitates careful consideration of body surface area, pharmacological, physiological and anatomical factors, pharmacokinetic parameters, metabolic function, receptor, and life span. The concept of estimating the first-in-human dose, interspecies scaling between species and the factors influencing the dose escalation were reviewed. The pros and cons of various approaches to determine first-in-human dose including allometric scaling, pharmacokinetically guided approach, minimal anticipated biological effect level, pharmacokinetic-pharmacodynamic modeling, similar drug approach, and microdosing were explained. The five steps to estimate maximum recommended starting dose for human studies by scaling factor were elaborated. Few examples, illustrating the application of different approaches were also demonstrated along with concerns that may be considered while applying such methods. Furthermore, typical considerations in dose administration, dosing through diet, maximum absorbable dose, blood sampling, and anesthesia in animal species were discussed. In summary, this review may serve as a concise guide for predicting human equivalent dose from animal species for researchers involved in various phases of preclinical and early clinical drug development.

Netarsudil: A new ophthalmic drug in the treatment of chronic primary open angle glaucoma and ocular hypertension.

BACKGROUND: Vision impairment remains a major health problem worldwide. Elevated intraocular pressure is a prime risk factor for blindness in the elderly. Netarsudil is a Rho-associated protein kinase (ROCK) inhibitor, which also inhibits norepinephrine transport. This narrative review summarizes the properties and clinical significance of netarsudil, a promising drug in topical glaucoma therapy. METHODS: We searched PubMed, Medline and Scopus databases using relevant keywords to retrieve information on the physicochemical properties, formulation, mechanism of action, clinical pharmacokinetics, dose and toxicity of netarsudil. RESULTS: Netarsudil showed promising effects in lowering the elevated intraocular pressure by two mechanisms. The US FDA approved netarsudil for clinical use in 2017 under the trademark of Rhopressa® while European Medicines Agency approved Rhokiinsa® in 2019. This drug is available as a 0.02% ophthalmic solution for once-daily topical application. CONCLUSION: The discovery of netarsudil is a breakthrough in the therapy of glaucoma with proven efficacy in a wide range of eye pressures and is well tolerated in cases with ocular hypertension and chronic glaucoma.

Enhancement in antinociceptive and anti-inflammatory effects of tramadol by transdermal proniosome gel.

Oral therapy of tramadol, an opiate analgesic, undergoes extensive hepatic metabolism and requires frequent administration. Transdermal therapy by virtue can overcome these issues and can improve the efficacy and reduce abuse liability of tramadol. The aim of this research was to investigate the possibility of transdermal delivery of tramadol by formulating proniosome gel and evaluate its therapeutic potential in vivo. The effect of formulation composition as well as amount of drug on physicochemical characteristics of prepared proniosomes were examined. Best proniosome gel (F4) was selected and evaluated for drug release, stability and transdermal efficacy by ex vivo and in vivo experiments. The vesicles demonstrated optimal properties including spherical shape, nanosize with good entrapment efficiency, adequate zeta potential, higher stability and greater transdermal flux. The amorphization and dispersion of tramadol in the aqueous core of proniosome vesicles was confirmed by differential scanning calorimeter. Release profile of F4 was distinct (P < 0.001) from control and displayed steady and prolonged tramadol release by Fickian diffusion. Transdermal therapy of F4 showed prominent reduction of induced twitches (P < 0.005) in mice and edema (P < 0.05) in rats, as compared to oral tramadol. The improvement in clinical efficacy of tramadol in transdermal therapy is correlated with the pharmacokinetic data observed. In conclusion, the observed improvement in antinociceptive and anti-inflammatory effects from proniosome carriers signifies its potential to be a suitable alternative to oral therapy of tramadol with greater efficacy.

Nanoemulsion Based Vehicle for Effective Ocular Delivery of Moxifloxacin Using Experimental Design and Pharmacokinetic Study in Rabbits.

Nanoemulsion is one of the potential drug delivery strategies used in topical ocular therapy. The purpose of this study was to design and optimize a nanoemulsion-based system to improve therapeutic efficacy of moxifloxacin in ophthalmic delivery. Moxifloxacin nanoemulsions were prepared by testing their solubility in oil, surfactants, and cosurfactants. A pseudoternary phase diagram was constructed by titration technique and nanoemulsions were obtained with four component mixtures of Tween 80, Soluphor® P, ethyl oleate and water. An experiment with simplex lattice design was conducted to assess the influence of formulation parameters in seven nanoemulsion formulations (MM1-MM7) containing moxifloxacin. Physicochemical characteristics and in vitro release of MM1-MM7 were examined and optimized formulation (MM3) was further evaluated for ex vivo permeation, antimicrobial activity, ocular irritation and stability. Drug pharmacokinetics in rabbit aqueous humor was assessed for MM3 and compared with conventional commercial eye drop formulation (control). MM3 exhibited complete drug release in 3 h by Higuchi diffusion controlled mechanism. Corneal steady state flux of MM3 (~32.01 µg/cm2/h) and control (~31.53 µg/cm2/h) were comparable. Ocular irritation study indicated good tolerance of MM3 and its safety for ophthalmic use. No significant changes were observed in the physicochemical properties of MM3 when stored in the refrigerator for 3 months. The greater aqueous humor concentration (Cmax; 555.73 ± 133.34 ng/mL) and delayed Tmax value (2 h) observed in MM3 suggest a reduced dosing frequency and increased therapeutic efficacy relative to control. The area under the aqueous humor concentration versus time curve (AUC0-8 h) of MM3 (1859.76 ± 424.51 ng·h/mL) was ~2 fold higher (p < 0.0005) than the control, suggesting a significant improvement in aqueous humor bioavailability. Our findings suggest that optimized nanoemulsion (MM3) enhanced the therapeutic effect of moxifloxacin and can therefore be used as a safe and effective delivery vehicle for ophthalmic therapy.

Effective Therapeutic Delivery and Bioavailability Enhancement of Pioglitazone Using Drug in Adhesive Transdermal Patch.

The administration of pioglitazone as an oral therapy is restricted due to various challenges. The aim of the current investigation was to evaluate the suitability of pioglitazone in adhesive transdermal patch as an alternative delivery system, in order to improve therapeutic delivery. Drug in adhesive pioglitazone (2% w/w) transdermal patch were optimized for drug release, suitable adhesive, and skin permeation enhancer. The selected patch was examined for drug-loading capacity and the patch with greater pioglitazone (6% w/w) was evaluated in rat models. The release of pioglitazone was influenced by the tested adhesive and was shown to be significantly higher (p < 0.001) with patch, prepared using Duro-Tak 87-2516. The ex vivo permeation results substantiate the release data as a greater transdermal flux (15.67 ± 2.35 µg/cm2/h) was demonstrated in patch fabricated with Duro-Tak 87-2516. Skin penetration enhancers promoted the ex vivo transdermal delivery of pioglitazone, and was ~2 folds (p < 0.0001) higher with propylene glycol, as compared to patch without enhancer. The maximum solubility of pioglitazone in Duro-Tak 87-2516 was found to be 6% w/w. Increasing the drug content in patch enhanced the transdermal flux and was highest when the pioglitazone level was 6% w/w (72.68 ± 5.76 µg/cm2/h). In vivo pharmacokinetic data demonstrate that the AUC0-α in transdermal application (13,506.51 ± 1649.92 ng·h/mL) was ~2 times higher (p < 0.0001) as compared to oral dosage form. In conclusion, the promising results observed here signifies that developed patch could be a viable alternative for oral therapy of pioglitazone.