Ayyappa Chaturvedula

Iontophoretic in Vivo Transdermal Delivery of β-Blockers in Hairless Rats and Reduced Skin Irritation by Liposomal Formulation

AbstractPurpose. To demonstrate the in vivo transdermal delivery and establish the comparative pharmacokinetics of five β-blockers in hairless rat. Methods. Intravenous dosing was initially done via jugular cannula. For iontophoretic delivery, current (0.1 mA/cm2) was applied for 2 h through a drug reservoir patch containing the β-blocker (10 mg/ml). Blood samples were collected and analyzed by stereoselective HPLC assays. Any irritation resulting from patch application was quantified by a chromameter. Multilamellar liposomal formulation was prepared by the thin-film hydration method and converted to unilamellar liposomes by extrusion. Results. With transdermal iontophoresis, therapeutically relevant amounts of propranolol (83.78 ± 7.4 ng/ml) were delivered within an hour and lasted for up to 4 h. Cmax (185.1 ± 56.8 ng/ml) was reached at hour 3. A significantly higher amount (p < 0.05) of sotalol HCl was delivered compared to other β-blockers. There was no significant difference in the S/R ratio of AUC0-t for enantiomers after both intravenous and transdermal delivery. Skin irritation was significantly reduced (p < 0.05) when a liposomal formulation of the propranolol base was used rather than the base itself. Conclusions. The comparative pharmacokinetics of intravenous and transdermal iontophoretic delivery of five β-blockers in hairless rats was established. It was shown that there is no stereoselective permeation.

Population pharmacokinetics of tenofovir and tenofovir-diphosphate in healthy women

The objective of this analysis was to develop and qualify a population pharmacokinetic model describing plasma tenofovir (TFV) concentrations and tenofovir‐diphosphate (TFV‐DP) concentrations in peripheral blood mononuclear cell (PBMC) in healthy women volunteers from the MTN‐001 clinical trial, an open label 3‐way crossover study of oral tenofovir disoproxil fumarate 300 mg tablet, TFV 1% vaginal gel, or both. TFV pharmacokinetics were best described by a 2‐compartment, first‐order absorption/elimination model with absorption lag time. TFV was linked to PBMC TFV‐DP by first‐order uptake with first‐order elimination. An adherence adjustment was included to account for nonadherence by explicitly modeling a bioavailability parameter on the previous days dose. The final model included weight as a covariate on central compartment volume (Vc) with estimates as follows: absorption rate constant (Ka) 9.79 h−1, absorption lag time 0.5 hours, Vc 385.71–2.16*(73‐WT(kg)), and apparent TFV clearance of 56.7 L/h ((K20 + K24)*Vc). TFV‐DPs half‐life was 53.3 hours. All diagnostic plots and bootstrap confidence intervals were acceptable. Model validation was conducted using simulations compared to data from the MTN‐001 oral + vaginal period and other clinical trial data. The resulting model closely predicted the disposition of TFV and TFV‐DP when compared to healthy participant data from another clinical trial.

Linking the population pharmacokinetics of tenofovir and its metabolites with its cellular uptake and metabolism.

Empirical pharmacokinetic models are used to explain the pharmacokinetics of the antiviral drug tenofovir (TFV) and its metabolite TFV diphosphate (TFV-DP) in peripheral blood mononuclear cells. These empirical models lack the ability to explain differences between the disposition of TFV-DP in HIV-infected patients vs. healthy individuals. Such differences may lie in the mechanisms of TFV transport and phosphorylation. Therefore, we developed an exploratory model based on mechanistic mass transport principles and enzyme kinetics to examine the uptake and phosphorylation kinetics of TFV. TFV-DP median Cmax from the model was 38.5 fmol/106 cells, which is bracketed by two reported healthy volunteer studies (38 and 51 fmol/106 cells). The model presented provides a foundation for exploration of TFV uptake and phosphorylation kinetics for various routes of TFV administration and can be updated as more is known on actual mechanisms of cellular transport of TFV. CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e147; doi:10.1038/psp.2014.46; published online 12 November 2014.Empirical pharmacokinetic models are used to explain the pharmacokinetics of the antiviral drug tenofovir (TFV) and its metabolite TFV diphosphate (TFV‐DP) in peripheral blood mononuclear cells. These empirical models lack the ability to explain differences between the disposition of TFV‐DP in HIV‐infected patients vs. healthy individuals. Such differences may lie in the mechanisms of TFV transport and phosphorylation. Therefore, we developed an exploratory model based on mechanistic mass transport principles and enzyme kinetics to examine the uptake and phosphorylation kinetics of TFV. TFV‐DP median Cmax from the model was 38.5 fmol/106 cells, which is bracketed by two reported healthy volunteer studies (38 and 51 fmol/106 cells). The model presented provides a foundation for exploration of TFV uptake and phosphorylation kinetics for various routes of TFV administration and can be updated as more is known on actual mechanisms of cellular transport of TFV.

Transdermal delivery of methotrexate for pediatrics using silicon microneedles

BACKGROUND The objective of this work was to study transdermal delivery of methotrexate using silicon microneedles and simulate plasma concentrations using a population pharmacokinetic model. RESULTS Characterization of silicon microneedles was carried out by scanning electron microscopy, transepidermal water loss, methylene blue staining, calcein imaging, pore permeability index and confocal microscopy, which confirmed the formation of microchannels. In vitro permeation studies were performed to study the enhancement in transdermal delivery following microporation. CONCLUSION Simulation data demonstrated that with 16, 64, 128 and 192 microneedles, mean plasma concentrations of 0.3, 1.4, 2.8 and 4.2 ng/ml, respectively, can be achieved. Thus, therapeutically relevant doses could be delivered in pediatrics by increasing the number of microneedles and patch area.

Estimation of tenofovir's population pharmacokinetic parameters without reliable dosing histories and application to tracing dosing history using simulation strategies.

The objectives of this analysis were to develop a population pharmacokinetic model (PPK) for tenofovir without using potentially unreliable patient reported dosing records and to retrace patient dosing history using pharmacokinetic simulations conditioned on protocol design constraints to assess patient adherence. MTN‐001 is a multi‐center, open label, 3‐way cross over study comparing oral, vaginal and combination (oral and vaginal) administration of tenofovir in healthy women. It was reported that self‐reported adherence in this study was high (94%), but serum concentrations indicated only 64% of participants used tablets consistently. A method based on superposition was applied to develop the population PPK considering only observable clinic visit dosing information. A two compartment model described the data well and the parameters agree with the literature reported values. Race was not a significant covariate on clearance. Retracing of the dosing history with 3‐past dose resolution was not successful. Trial simulations with full adherence assumption predict a median Cmin of 68 ng/mL, which is in agreement with literature reports. Non‐adherence at 25% resulted in 37–51% reduction in Cmin using one coin and two coin models, respectively. Population analyses should consider some method of correction for non‐adherence to avoid biased estimates.

Population pharmacokinetics of tenofovir in HIV-1-uninfected members of serodiscordant couples and effect of dose reporting methods

ABSTRACT Antiretroviral preexposure prophylaxis (PrEP) with once-daily dosing of tenofovir and tenofovir-emtricitabine was shown to be effective for preventing HIV-1 infection in individuals who had HIV-1-seropositive partners (the Partners PrEP Study). We developed a population pharmacokinetic model for tenofovir and investigated the impacts of different dose reporting methods. Dosing information was collected as patient-reported dosing information (PRDI) from 404 subjects (corresponding to 1,280 drug concentration records) from the main trial and electronic monitoring-based adherence data collected from 211 subjects (corresponding to 327 drug concentration records) in an ancillary adherence study. Model development was conducted with NONMEM (7.2), using PRDI with a steady-state assumption or using PRDI replaced with electronic monitoring records where available. A two-compartment model with first-order absorption was the best model in both modeling approaches, with the need for an absorption lag time when electronic monitoring-based dosing records were included in the analysis. Age, body weight, and creatinine clearance were significant covariates on clearance, but only creatinine clearance was retained in the final models per stepwise selection. Sex was not a significant covariate on clearance. Tenofovir population pharmacokinetic parameter estimates and the precisions of the parameters from the two final models were comparable with the point estimates of the parameters, differing from 0% to 35%, and bootstrap confidence intervals widely overlapped. These findings indicate that PRDI was sufficient for population pharmacokinetic model development in this study, with a high level of adherence per multiple measures.

Investigation of the Dermal Absorption and Irritation Potential of Sertaconazole Nitrate Anhydrous Gel

Effective topical therapy of cutaneous fungal diseases requires the delivery of the active agent to the target site in adequate concentrations to produce a pharmacological effect and inhibit the growth of the pathogen. In addition, it is important to determine the concentration of the drug in the skin in order to evaluate the subsequent efficacy and potential toxicity for topical formulations. For this purpose, an anhydrous gel containing sertaconazole nitrate as a model drug was formulated and the amount of the drug in the skin was determined by in vitro tape stripping. The apparent diffusivity and partition coefficients were then calculated by a mathematical model describing the dermal absorption as passive diffusion through a pseudo-homogenous membrane. The skin irritation potential of the formulation was also assessed by using the in vitro Epiderm™ model. An estimation of the dermal absorption parameters allowed us to evaluate drug transport across the stratum corneum following topical application. The estimated concentration for the formulation was found to be higher than the MIC100 at the target site which suggested its potential efficacy for treating fungal infections. The skin irritation test showed the formulation to be non-irritating in nature. Thus, in vitro techniques can be used for laying the groundwork in developing efficient and non-toxic topical products.

Markov Mixed Effects Modeling Using Electronic Adherence Monitoring Records Identifies Influential Covariates to HIV Preexposure Prophylaxis

Adherence is a major factor in the effectiveness of preexposure prophylaxis (PrEP) for HIV prevention. Modeling patterns of adherence helps to identify influential covariates of different types of adherence as well as to enable clinical trial simulation so that appropriate interventions can be developed. We developed a Markov mixed‐effects model to understand the covariates influencing adherence patterns to daily oral PrEP. Electronic adherence records (date and time of medication bottle cap opening) from the Partners PrEP ancillary adherence study with a total of 1147 subjects were used. This study included once‐daily dosing regimens of placebo, oral tenofovir disoproxil fumarate (TDF), and TDF in combination with emtricitabine (FTC), administered to HIV‐uninfected members of serodiscordant couples. One‐coin and first‐ to third‐order Markov models were fit to the data using NONMEM® 7.2. Model selection criteria included objective function value (OFV), Akaike information criterion (AIC), visual predictive checks, and posterior predictive checks. Covariates were included based on forward addition (α = 0.05) and backward elimination (α = 0.001). Markov models better described the data than 1‐coin models. A third‐order Markov model gave the lowest OFV and AIC, but the simpler first‐order model was used for covariate model building because no additional benefit on prediction of target measures was observed for higher‐order models. Female sex and older age had a positive impact on adherence, whereas Sundays, sexual abstinence, and sex with a partner other than the study partner had a negative impact on adherence. Our findings suggest adherence interventions should consider the role of these factors.