Convolution- and Deconvolution-Based Approaches for Prediction of Pharmacokinetic Parameters of Diltiazem Extended-Release Products in Flow-Through Cell Dissolution Tester.

The present study evaluated the effect of different configuration setups of the Flow-Through Cell (USP IV) dissolution tester in developing in vitro-in vivo correlation (IVIVC). A Biopharmaceutics Classification System (BCS) Class I Diltiazem (DTZ), formulated in extended-release (ER) gel-matrix system, was employed for this purpose. The study also assessed the validity and predictability of IVIVC employing both deconvolution- and convolution-based approaches. In vitro release was conducted in USP IV as open- or closed-loop setups, while the pharmacokinetic (PK) data were obtained from a previous fasted-state cross-over study conducted on 8 healthy male volunteers, after oral administration of ER matrix tablets against market product (Tildiem Retard® 90 mg). PK parameters (Cmax, AUC0-t and AUC0-∞) were predicted, and compared with actual data to establish the strength of correlation models. Results showed that DTZ release from ER products was influenced by operating the FTC in different configuration-setups, where ≥ 75% of labeled DTZ was released after 6 h and 12 h using the open- and closed-loop settings, respectively. Correlation between fraction-dissolved versus fraction-absorbed for both ER products displayed linear relation upon employing FTC open-loop setup. Convolution-based approach was more discriminative in predicting DTZ in vivo PK parameters with a minimal prediction error, compared to deconvolution-based approach. A successful trial to predict DTZ PKs from individual in vitro data performed in USP IV dissolution model was established, employing convolution technique. Basic principle of the convolution approach provides a simple and practical method for developing IVIVC, hence could be utilized for other BCS Class I extended-release drug products.

Enhanced Oral Bioavailability of Diltiazem by the Influence of Gallic Acid and Ellagic Acid in Male Wistar Rats: Involvement of CYP3A and P-gp Inhibition.

The oral bioavailability of diltiazem is very low due to rapid first pass metabolism in liver and intestine. The purpose of the study was to investigate the effect of gallic acid and ellagic acid on intestinal transport and oral bioavailability of diltiazem in rats. The intestinal transport and permeability of diltiazem was evaluated by in vitro non-everted sac method and in situ single pass intestinal perfusion study. The oral pharmacokinetics was evaluated by conducting oral bioavailability study. The intestinal transport and apparent permeability of diltiazem were significantly enhanced in duodenum, jejunum, and ileum of gallic and ellagic acid-treated groups. The effective permeability of diltiazem was significantly enhanced in ileum part of gallic and ellagic acid-treated groups. When compared with control group, the presence of these two phytochemicals significantly enhanced the area under plasma concentration-time curve and the peak plasma concentration of diltiazem (Cmax ). Gallic acid and ellagic acid significantly increased the bioavailability of diltiazem due to the inhibition of both CYP3A-mediated metabolism and P-glycoprotein-mediated efflux in the intestine and/or liver. Based on these results, the clinical experiments are warranted for the confirmation to reduce the dose of diltiazem when concomitantly administered with these phytochemicals. Copyright © 2017 John Wiley & Sons, Ltd.

Significant impacts of CYP3A4*1G and CYP3A5*3 genetic polymorphisms on the pharmacokinetics of diltiazem and its main metabolites in Chinese adult kidney transplant patients.

WHAT IS KNOWN AND OBJECTIVE: The calcium channel blocker diltiazem has been used widely as a cyclosporine (CsA)/tacrolimus-sparing agent. However, considerable interpatient variability in diltiazem's CsA/tacrolimus-sparing effect has been observed in many clinical studies. This study was carried out to investigate the impacts of the CYP3A4*1G and CYP3A5*3 genetic polymorphisms on the trough concentration/dose ratios and pharmacokinetics of diltiazem and its main metabolites in Chinese adult renal transplant patients. METHODS: Two hundred and twenty-five Chinese renal transplant patients were genotyped for CYP3A4*1G and CYP3A5*3. The predose and post-dose plasma concentrations of diltiazem and its main metabolisms were determined by HPLC. The relationships between the genotypes and pharmacokinetics were investigated. RESULTS AND DISCUSSION: The dose-adjusted concentrations and pharmacokinetics of diltiazem and its main metabolites were significantly affected by CYP3A4 *1G and CYP3A5*3 alleles. Patients with a CYP3A4*1/*1 genotype were found to have a higher dose-adjusted trough concentration and AUC of diltiazem and its main metabolites compared with those with CYP3A4*1G*1G(P<0·05). The dose-adjusted trough levels and AUC of diltiazem and its main metabolites were significantly lower in CYP3A5*1*1 carriers than in CYP3A5*3 carriers (P < 0·05). WHAT IS NEW AND CONCLUSION: The CYP3A4*1G and CYP3A5*3 genetic polymorphisms are closely related to the trough concentration/dose ratios and pharmacokinetics of diltiazem and its main metabolites in Chinese adult renal transplant patients.

Characterization of Species Differences in Tissue Diltiazem Deacetylation Identifies Ces2a as a Rat-Specific Diltiazem Deacetylase.

Diltiazem, a calcium channel blocker, is mainly metabolized via demethylation or deacetylation in humans. Diltiazem demethylation is catalyzed by cytochrome P450 2D6 and 3A4. Although it was previously reported that the area under the curve ratio of deacetyldiltiazem to diltiazem after oral dosing with diltiazem in rats was sevenfold higher than in humans, the molecular mechanisms underlying this species difference remain to be clarified. In the present study, we compared the diltiazem deacetylase activity in liver, intestinal, renal, and pulmonary microsome preparations of human and experimental animal tissues to identify the specific deacetylase enzyme(s) involved in deacetylation. Diltiazem deacetylase activity was detected in rat liver and small intestine microsome preparations, but not in those from human, monkey, dog, and mouse tissues. Further purification of rat liver microsome (RLM) proteins identified four carboxylesterase (Ces) enzymes (Ces1d, Ces1e, Ces1f, and Ces2a) as potential candidate deacetylases. On the basis of their tissue distribution, the Ces2a enzyme was considered to be the enzyme that was responsible for diltiazem deacetylation. Furthermore, recombinant rat Ces2a expressed in Sf21 cells displayed efficient diltiazem deacetylase activity with similar Km values as RLM. In addition, the inhibitory characteristics of various chemical inhibitors were similar between recombinant rat Ces2a and RLM. In conclusion, we determined that only rat tissues were able to catalyze diltiazem deacetylation. The characterization of Ces enzymes in animal species, as undertaken in this study, will prove useful to predict the species-specific pharmacokinetics differences between the in vivo models used for drug development.

Liposomal diltiazem HCl as ocular drug delivery system for glaucoma.

In this study, unilamellar liposomal vesicles of diltiazem HCl (DH) were prepared using either reversed phase evaporation (REV) or proliposome methods. Soya phosphatidylcholine (SPC) was used for preparing the liposomes, and the vesicles were rigidified using cholesterol (Chol) or cetyl alcohol (CA) in different molarities. The major differences in both the entrapment efficiency percent (EE%) and drug release were evaluated as a function of the method of preparation, Chol or CA contents, and charging lipids. Moreover, the morphology of the vesicles was confirmed by transmission electron microscopy. The effects of Chol or CA incorporation into the liposomes were discussed based on thermal analysis. The in vivo evaluation of liposomal DH was assessed using intra-ocular pressure (IOP), reducing effects in rabbit eyes. Liposomes prepared via REV exhibited higher EE% and lower release rates when compared with those prepared from proliposomes. The incorporation of either Chol or CA in the liposomes enhanced the EE% and decreased the release rates; however, Chol yielded higher results than CA. In addition, both dicetyl phosphate (DCP; negative charge inducer) and stearyl amine (SA, positive charge inducer) decreased the EE% and increased the DH release rate. The in vivo antiglaucoma effects of the liposomes were calculated according to the area above the IOP/Time curve, the maximum response and the time for the maximum response and were compared with effects of the DH solution. The results were in the following order: DH solution < SPC/CA (REV) < SPC/Chol/DCP(REV) < SPC/Chol (proliposomes) < SPC/Chol/SA(REV) < SPC/Chol (REV).

Novel orally swallowable IntelliCap(®) device to quantify regional drug absorption in human GI tract using diltiazem as model drug.

Typically, colonic absorption of a drug is mandatory for a sustained release formulation to hold the drug's plasma level for more than 12 or 24 h above the minimum therapeutic plasma concentration (efficacy). According to Drugs@FDA, only 7.4% of the oral drugs are extended release forms probably showing colonic absorption. Therefore an early determination of a drug's colonic absorption using the IntelliCap® in animals or humans will provide the mandatory information to initiate or stop a SR form development. Diltiazem (60 mg) is used in the oral swallowable IntelliCap® and the marketed SR form from Mylan (coated beads). A human study with 14 healthy volunteers compared the Mylan formulation with the IntelliCap® device that releases the drug identical to the in-vitro dissolution of the Mylan product. The plasma profiles of IntelliCap® and Mylan formulation are highly similar. The mean AUC (bioequivalence fulfilled) and mean Cmax of IntelliCap® shows only a difference of +15% and -12%, respectively. But the PK profile of the Mylan formulation shows a broader peak around Cmax. About 81.8% diltiazem was absorbed in the colon (IntelliCap®) comparable to former publications. The Mylan is a SR diffusion coated beads form whereas the IntelliCap® is a monolithic capsule. The beads are transported in the gut and spread which results in a longer Tmax and a broader Cmax peak. The IntelliCap® device can quantitatively measure the colonic absorption of a drug in excellent accordance to a standard oral SR dosage form.

In vitro and in vivo evaluation of a novel diltiazem hydrochloride polydispersity sustained-release system.

OBJECTIVE: To microencapsulate diltiazem hydrochloride (DH) drug-resin to obtain obvious sustained release effect in vitro and in vivo. METHODS: The drug-resinates were made by bath method. The drug-resinates microcapsules were prepared with the ratio of the concentration of coating materials being 1% and the ratio of drug-resin complexes to coating materials being 10:1 by emulsion-solvent diffusion method. The pharmacokinetic of the sustained-release DH microspheres in beagle dogs was carried out. RESULTS: The microencapsulated ion-exchange resin beads containing DH showed sustained-release characteristics for 12 h and exhibited complete release. The pharmacokinetics parameters of DH sustained-release microspheres and reference tablet was AUC0-24 (ng · h · mL(-1)) 836.3 and 857.3, C(max) (ng · mL(-1)) 85.4 and 135.2, T(max) (h) 4.7 and 1.2. CONCLUSION: The mononucleated microencapsulated ion-exchange resin beads showed obvious sustained release character in vitro. The pharmacokinetic of the DH microspheres showed that the test dosage forms were bioequivalent with reference dosage form and had an obviously sustained release effect in vivo.

Effects of CYP3A5 and CYP2D6 genetic polymorphism on the pharmacokinetics of diltiazem and its metabolites in Chinese subjects.

PURPOSE: To assess the possibility of using CYP2D6 10 +/- CYP3A5*3 as biomarkers to predict the pharmacokinetics of diltiazem and its two metabolites among healthy Chinese subjects. METHODS 41 healthy Chinese were genotyped for CYP3A5 3 and CYP2D6 10, and then received a single oral dose of diltiazem hydrochloride capsules (300 mg). Multiple blood samples were collected over 48 h, and the plasma concentrations of diltiazem, N-desmethyl diltiazem and desacetyl diltiazem were determined by HPLC-MS/MS. The relationships between the genotypes and pharmacokinetics were investigated. RESULTS: The pharmacokinetics of diltiazem, N-desmethyl diltiazem were not significantly affected by both CYP3A5 3 and CYP2D6*10 alleles. However, the systemic exposure of the pharmacologyically active metabolites, desacetyl diltiazem, was 2-fold higher in CYP2D6 10/10 genotype carriers than in 1/10 or 1/1 ones (AUC(o-inf) of CYP2D6 1/1, 1/10 and 10/10 are 398.2 +/- 162.9, 371,0 69.2 and 726.2 +/- 468.1 respectively, p <0.05). CONCLUSIONS: Two of the most frequent alleles, CYP3A5 3 and CYP2D6 10, among Chinese do not have major impacts on the disposition of diltiazem and N-desmethyl diltiazem. However, the desacetyl diltiazem showed 2-fold accumulation in individuals with CYP2D6 10/10 genotype. Despite this, the effect of genotype of CYP2D6 on clinical outcome of diltiazem treatment is expected to be limited.

Repeated dosing of piperine induced gene expression of P-glycoprotein via stimulated pregnane-X-receptor activity and altered pharmacokinetics of diltiazem in rats.

This study investigated the effect of piperine on the gene expression of P-glycoprotein (P-gp) as well as pregnane-X-receptor (PXR) activity and also its implication on the bioavailability of diltiazem, a P-gp substrate. The effect of piperine on the systemic exposure of diltiazem was examined in rats after the intravenous and oral administration of diltiazem with/without 2 week pretreatment with piperine. Compared with the control group given diltiazem (20 mg/kg) alone, the pretreatment with piperine (10 or 20 mg/kg, once daily for 2 weeks) decreased the oral exposure of diltiazem by 36-48% in rats. Consequently, the bioavailability of oral diltiazem was significantly lower (p < 0.05) after the 2 week pretreatment with piperine. The pretreatment with piperine for 2 weeks also reduced the systemic exposure of desacetyldiltiazem, a major active metabolite of diltiazem by approximately 73%, accompanied by a significant decrease in the metabolite-parent ratio. In contrast to the oral pharmacokinetics, piperine did not affect the intravenous pharmacokinetics of diltiazem in rats. Immunoblot analysis indicated that the protein expression level of intestinal P-gp was significantly enhanced after the 2 week pretreatment with piperine in rats. In addition, piperine increased the PXR reporter activity in human hepatoma cells. Taken together, the 2 week pretreatment with piperine significantly induced intestinal P-gp expression in conjunction with stimulated PXR activity and decreased the oral exposure of diltiazem and desacetyldiltiazem in rats.

Improved effectiveness of biochanin A as a P-gp inhibitor in solid dispersion.

The present study aimed to improve the in vivo effectiveness of biochanin A as a P-gp inhibitor by formulation in solid dispersion (SD). SDs were prepared with Solutol HS15 and hydroxypropylmethyl cellulose (HPMC2910) and their inhibition effect on P-gp mediated cellular efflux was examined by using NCI/ADR-RES cells overexpressing P-gp. Compared to the untreated biochanin A, SD formulations enhanced significantly (p < 0.01) the cellular uptake of rhodamine-123, a P-gp substrate by approximately 2-3 folds in NCI/ADR-RES cells. Furthermore, the oral and intravenous pharmacokinetics of diltiazem, a P-gp substrate as well as its active metabolite, desacetyldiltiazem, was determined in rats after pretreatment with biochanin A. Pretreatment with biochanin A in a SD formulation significantly (p < 0.05) increased the AUC of desacetyldiltiazem by 3-fold, although the oral exposure of diltiazem was not altered. In contrast, the intravenous pharmacokinetics of diltiazem and desacetyldiltiazem were not changed by the concurrent use of biochanin A, implying that oral biochanin A affected mainly the intestinal absorption of diltiazem rather than the hepatic extraction. In conclusion, SD formulation improved the in vivo effectiveness of biochanin A as a P-gp inhibitor.

Dose tailoring of tacrolimus based on a non-linear pharmacokinetic model in children with refractory nephrotic syndrome.

The population pharmacokinetics (PPK) of tacrolimus (TAC) in children with refractory nephrotic syndrome (RNS) have not been well-characterized. This study aimed to investigate the significant factors affecting the TAC PPK characteristics of children with RNS and to optimize the dosing regimen. A total of 494 concentrations from 108 children were obtained from routine therapeutic drug monitoring between 2016 and 2018. Information regarding the demographic features, laboratory test results, genetic polymorphisms of CYP3A5 (rs776746) and co-therapy medications were collected. PPK analysis was performed using the nonlinear mixed-effects modelling (NONMEM) software and two modelling strategies (the linear one-compartment model and nonlinear Michaelis-Menten model) were evaluated and compared. CYP3A5 genotype, weight, daily dose of TAC and daily dose of diltiazem were retained in the final linear model. The absorption rate constant (Ka) was set at 4.48 h-1 in the linear model, and the apparent clearance (CL/F) and volume of distribution (V/F) in the final linear model were 14.2 L/h and 172 L, respectively. CYP3A5 genotype, weight and daily dose of diltiazem were the significant factors retained in the final nonlinear model. The maximal dose rate (Vmax) and the average steady-state concentration at half-Vmax (Km) in the final nonlinear model were 2.15 mg/day and 0.845 ng/ml, respectively. The nonlinear model described the pharmacokinetic data of TAC better than the linear model in children with RNS. A dosing regimen was proposed based on weight, CYP3A5 genotype and daily dose of diltiazem according to the final nonlinear PK model, which may facilitate individualized drug therapy with TAC.

Tracing multiscale mechanisms of drug disposition in normal and diseased livers.

Hepatic drug disposition is different in normal and diseased livers. Different disease types alter disposition differently. What are the responsible micromechanistic changes and how do they influence drug movement within the liver? We provide plausible, concrete answers for two compounds, diltiazem and sucrose, in normal livers and two different types of cirrhotic rat livers: chronic pretreatment of rats with carbon tetrachloride (CCl(4)) and alcohol caused different types of cirrhosis. We started with simulated disposition data from normal, multilevel, physiologically based, object-oriented, discrete event in silico livers (normal ISLs) that validated against diltiazem and sucrose disposition data from normal livers. We searched the parameter space of the mechanism and found three parameter vectors that enabled matching the three wet-lab data sets. They specified micromechanistic transformations that enabled converting the normal ISL into two different types of diseased ISLs. Disease caused lobular changes at three of six levels. The latter provided in silico disposition data that achieved a prespecified degree of validation against wet-lab data. The in silico transformations from normal to diseased ISLs stand as concrete theories for disease progression from the disposition perspective. We also developed and implemented methods to trace objects representing diltiazem and sucrose during disposition experiments. This allowed valuable insight into plausible disposition details in normal and diseased livers. We posit that changes in ISL micromechanistic details may have disease-causing counterparts.

In-vitro and in-vivo characteristics of a modified-release double-pulse formulation for a water soluble drug.

OBJECTIVE: The aim of the present study was to evaluate the in-vitro dissolution and in-vivo pharmacokinetic profile of a novel two-phase modified-release formulation for diltiazem hydrochloride, as a water-soluble drug. MATERIALS AND METHODS: The delivery system consisted of two tablets inserted into a capsule. Both tablets comprised a coated drug core-matrix. The coating of the first tablet was intended to produce a first phase with a relatively fast release profile, while that of the second tablet included a unique controlling membrane designed to achieve a delayed controlled-release profile. Three different formulations were tested for their dissolution profiles both in water media and in buffer with a pH of 6.8. These formulations were also evaluated for their pharmacokinetic profile in healthy volunteers after single administration of a 240 mg dose. Serial venous blood samples were collected over 36 h post administration to measure diltiazem levels by HPLC. In addition the in-vivo /in-vitro correlation (IVIVC) was calculated for these formulations. RESULTS: The in-vitro characteristics of these formulations demonstrated a controlled release profile in both media but with different characteristics, as in Formulation 3 where faster dissolution profile obtained in water but slower one in pH 6.8 buffer. In-vivo the pharmacokinetic profile of these formulations showed that arabinogalactan containing formulations achieved plasma levels which allow a once daily administration. IVIVC calculation demonstrated that dissolution tested in buffer 6.8 media better correlates with the percent absorbed in-vivo and the best results were achieved with the formulation containing the highest amount of polysaccharide in the coating. CONCLUSION: It is concluded that the developed formulations achieved a controlled release profile both in-vitro and in-vivo which are suitable for once-daily administration.

The relationship between the drug concentration profiles in plasma and the drug doses in the colon.

After the dosing of an extended-release (ER) formulation, compounds may exist in solutions at various concentrations in the colon because the drugs are released at various speeds from the ER dosage form. The aim of this study was to investigate the relationship between the drug concentration profiles in plasma and the drug doses in the colon. Several drug solutions of different concentrations were directly administered into the ascending colon of dogs using a lubricated endoscope, and the effects of the drug dose on colonic absorption were estimated. As a result, dose-dependency of colonic absorption varied from compound to compound. Although the relative bioavailability of colonic administration of diclofenac, metformin and cevimeline compared to oral administration was similar regardless of the drug doses in the colon, colonic absorption of diltiazem varied according to the doses. From the results of the co-administration of verapamil and fexofenadine, it was clear that diltiazem underwent extensive hepatic and gastrointestinal first-pass metabolism, resulting in a low area under the curves (AUC) at a low drug dose. During the design of oral ER delivery systems, a colonic absorption study of candidate compounds should be carried out at several solutions of different drug concentrations and assessed carefully.

The effect of permeation enhancers on the viscosity and the release profile of transdermal hydroxypropyl methylcellulose gel formulations containing diltiazem HCl.

BACKGROUND AND METHOD: The objective of this study was to characterize the release of Diltiazem HCl (DTM HCl) from hydroxypropyl methylcellulose gels containing the following permeation enhancers at a 0.5% (w/w): sodium lauryl sulfate, dimethyl sulfoxide (DMSO), polysorbate 80, propylene glycol, N-methylpyrrolidone (NMP), fatty acids (oleic acid, caprylic acid, and myristic acid), and isopropyl myristate (IPM). The enhancers' effects on the gel's viscosity were also investigated. RESULTS: The novel findings of this study were the following: (i) polysorbate 80 was used for the first time as an enhancer with a hydrophilic compound in a hydrophilic carrier and it rendered the highest permeation flux (57.1 +/- 0.9 microg/cm(2)/h) compared with the rest of the enhancers, (ii) myristic acid (a 14-carbon-chain fatty acid) rendered the highest permeation flux (18.4 +/- 0.49 microg/cm(2)/h) among all fatty acids because of a decrease in the gel's viscosity, (iii) NMP (46.5 +/- 0.7 microg/cm(2)/h) and IPM (15.3 +/- 0.41 microg/cm(2)/h) increased the permeation flux from the second day onward. Both enhancers increased the gel's viscosity, (iv) sodium lauryl sulfate decreased the viscosity of the gel and the drug's permeation flux (8.1 +/- 0.21 microg/cm(2)/h) because of its binding with the drug, (v) propylene glycol decreased the permeation flux (10.2 +/- 0.32 microg/cm(2)/h) by increasing the gel viscosity, and (vi) DMSO increased the permeation flux (13.8 +/- 0.4 microg/cm(2)/h) without altering the viscosity. CONCLUSION: These findings indicate that to formulate DTM HCl into a hydroxypropyl methylcellulose gel the enhancers of choice should be polysorbate 80, myristic acid, DMSO, NMP, and IPM or combinations thereof.

Modulation of Drug Release from Natural Polymer Matrices by Response Surface Methodology: in vitro and in vivo Evaluation.

PURPOSE: The present work aimed at challenging the efficacy of natural gums, karaya and locust bean gum, as matrix-forming polymers for the formulation of sustained-release tablets of diltiazem, a model drug. METHODS: Central design composite was adopted for the formulation and optimization of tablet formulations. The two gums have been selected as independent variables. The dependent factors chosen were the amount of drug released in 1st hour (Y1), amount of drug released after 12 h (Y2), diffusion exponent (Y3), and time for half of the total drug released (T50%) (Y4). Wet granulation approach was used for the formulation of tablets. FT-IR, DSC, in vitro dissolution, swelling-erosion investigations, SEM, and stability studies were carried out. RESULTS AND DISCUSSION: It was evident that the release pattern from the prepared formulations was significantly influenced by the quantity of gum(s) in the tablet. FT-IR and DSC results confirm drug-polymer compatibility. Polynomial equations were used for the prediction of quantitative impact of independent factors at different levels on response variables. After ANOVA analysis, the significant factors were considered for constrained optimization to get the optimized formula. The optimized formula generated by the response surface methodology was evaluated both for in vitro and in vivo properties. The optimized formula and a sustained-release marketed product were subjected to in vivo studies in rabbits and the results of the t-test demonstrated insignificant variation in pharmacokinetic parameters among the two formulations, confirming that the prepared tablet showed sustained-release profile. CONCLUSION: The results indicated that karaya and locust bean gum can be effectively used to formulate sustained-release tablets.

Engineering of Nanospheres Dispersed Microneedle System for Antihypertensive Action.

BACKGROUND: A combinational therapy is mostly preferred in hypertension treatment because of low-dose and less side effects like pretibial edema, and gastrointestinal bleeding. OBJECTIVE: So the objective of the present work was to formulate an advanced drug delivery system in the form of bio-responsive microneedles by incorporating nifedipine, a cardiodepressant and diltiazem, a vasodilator for effective synergism in the treatment of hypertension. METHODS: The pH-responsive PLGA nanospheres of diltiazem were formulated using Water-in-Oil-in- Water (W/O/W) double emulsion and solvent-diffusion-evaporation technique. These nanospheres were added to nifedipine-PVP mixture and then incorporated into mold to develop microneedles. RESULTS: The microneedles showed the release of nifedipine almost 96.93± 2.31% for 24 h due to high PVP solubilization. The nanospheres of diltiazem on contact with acidic pH of skin managed to form of CO2 bubbles and increase the internal pressure to burst PLGA shell due to pore formation. The mean blood pressure observed for the normal group was 89.58 ± 3.603 mmHg, whereas the treatment with the new formulation significantly reduced the mean blood pressure up to 84.11 ± 2.98 mmHg in comparison to the disease control group (109.9 ± 1.825 mm Hg). CONCLUSION: This system co-delivers the drugs nifedipine and diltiazem in hypertension and shows an advance alternative approach over conventional drug delivery system.

Predicting Clinical Effects of CYP3A4 Modulators on Abemaciclib and Active Metabolites Exposure Using Physiologically Based Pharmacokinetic Modeling.

Abemaciclib, a selective inhibitor of cyclin-dependent kinases 4 and 6, is metabolized mainly by cytochrome P450 (CYP)3A4. Clinical studies were performed to assess the impact of strong inhibitor (clarithromycin) and inducer (rifampin) on the exposure of abemaciclib and active metabolites. A physiologically based pharmacokinetic (PBPK) model incorporating the metabolites was developed to predict the effect of other strong and moderate CYP3A4 inhibitors and inducers. Clarithromycin increased the area under the plasma concentration-time curve (AUC) of abemaciclib and potency-adjusted unbound active species 3.4-fold and 2.5-fold, respectively. Rifampin decreased corresponding exposures 95% and 77%, respectively. These changes influenced the fraction metabolized via CYP3A4 in the model. An absolute bioavailability study informed the hepatic and gastric availability. In vitro data and a human radiolabel study determined the fraction and rate of formation of the active metabolites as well as absorption-related parameters. The predicted AUC ratios of potency-adjusted unbound active species with rifampin and clarithromycin were within 0.7- and 1.25-fold of those observed. The PBPK model predicted 3.78- and 7.15-fold increases in the AUC of the potency-adjusted unbound active species with strong CYP3A4 inhibitors itraconazole and ketoconazole, respectively; and 1.62- and 2.37-fold increases with the concomitant use of moderate CYP3A4 inhibitors verapamil and diltiazem, respectively. The model predicted modafinil, bosentan, and efavirenz would decrease the AUC of the potency-adjusted unbound active species by 29%, 42%, and 52%, respectively. The current PBPK model, which considers changes in unbound potency-adjusted active species, can be used to inform dosing recommendations when abemaciclib is coadministered with CYP3A4 perpetrators.

Prediction of the effect of erythromycin, diltiazem, and their metabolites, alone and in combination, on CYP3A4 inhibition.

Predictive models of complex drug-drug interactions between multiple inhibitors and their metabolites have not been evaluated. The purpose of this study was to evaluate an interaction model for cytochrome P450 3A4 (CYP3A4) that incorporated the simultaneous reversible and irreversible inhibition by multiple inhibitors. Erythromycin (ERY) and diltiazem (DTZ), and their major metabolites, N-desmethylerythromycin (nd-ERY) and N-desmethyldiltiazem (nd-DTZ), were chosen to evaluate the model. k(inact) (rate constant for maximal inactivation), K(I) (inhibitor concentration at 50% maximal inactivation), and K(i) (reversible inhibition constant) were estimated for ERY, DTZ, nd-ERY, and nd-DTZ, respectively, using cDNA-expressed CYP3A4 and human liver microsomes under optimal experimental conditions. To evaluate the interaction model, combinations of inhibitors and metabolites were incubated at concentrations equal to K(I), (1/2)K(I), and 2K(I) of each inhibitor for specified durations in both enzyme systems. The models were further evaluated by the incubation of combinations of inhibitors with the substrate testosterone for 10 min. CYP3A4 inhibition in the presence of drug mixtures was predicted from the inhibition parameters determined for each drug or metabolite alone. The CYP3A4 activity in the presence of multiple inhibitors was well predicted by the model incorporating additive irreversible inhibition as modified by mutual competitive inhibition (percent mean error and percent mean absolute error ranged from -0.06 to 0.04 and from 0.03 to 0.09, respectively). In conclusion, the additive model predicted the combined effect of multiple inhibitors on CYP3A inhibition in vitro. However, simultaneous reversible and irreversible inhibition effects should be taken into account in a reaction mixture of substrate and multiple inhibitors of CYP3A4.

Semiphysiologically based pharmacokinetic models for the inhibition of midazolam clearance by diltiazem and its major metabolite.

Prediction of the extent and time course of drug-drug interactions (DDIs) between the mechanism-based inhibitor diltiazem (DTZ) and the CYP3A4 substrate midazolam (MDZ) is confounded by time- and concentration-dependent clearance of the inhibitor. Semiphysiologically based pharmacokinetic (PBPK) models were developed for DTZ and MDZ with the major metabolite of DTZ, N-desmethyldiltiazem (nd-DTZ), incorporated in the DTZ model. Enzyme kinetic parameters (k(inact) and K(I)) for DTZ and nd-DTZ were estimated in vitro and used to model the time course of changes in the amount of CYP3A4 in the liver and gut wall, which in turn, determined the nonlinear elimination of MDZ and DTZ, and the corresponding DDI. The robustness of the model prediction was assessed by comparing the results of the prediction to published DTZ pharmacokinetic and DTZ/MDZ interaction data. A clinical study was conducted to further validate the predicted increase of MDZ exposure after DTZ treatment. The model predicted the nonlinear disposition of DTZ after single and multiple oral doses. The clinical study showed that DTZ treatment resulted in 4.1- and 1.6-fold increases in MDZ exposure after oral and intravenous MDZ administration, respectively, suggesting that the DDI in the gut wall plays an important role in the DTZ/MDZ interaction. The semi-PBPK model incorporating the DDI at the gut wall, and the effect of nd-DTZ successfully predicted the nonlinear disposition of DTZ and its interaction with MDZ. Moreover, model simulation suggested that both DTZ and nd-DTZ contributed to the overall inhibitory effect after DTZ administration, and the values of the in vitro estimated inhibition parameters and CYP3A4 turnover rate are critical for the prediction.