Fixed Dose Single Tablet Formulation with Differential Release of Amlodipine Besylate and Simvastatin and Its Pharmacokinetic Profile: QbD and Risk Assessment Approach.

PURPOSE: A differential release fixed dose matrix tablet of amlodipine besylate (AML-B) and simvastatin (SIM) was formulated to enhance patient compliance. MATERIAL AND METHOD: In the first phase, release controlling parameters of AML-B and SIM granules were identified and in the second phase a fixed dose AML-B and SIM tablet formulation was prepared and optimized for a differential release of the drugs using a quality by design (QbD) and risk assessment approach. A validated HPLC method was employed for simultaneous determination of AML-B and SIM for FDC formulation. A pharmacokinetics of the above drugs was studied in healthy dogs in the third phase. RESULTS: In QbD-based optimized formulation, Eudragit® RSPO-dicalcium phosphate (DCP) blend controlled the release of AML-B over 8 h, though this diffusion-controlled release assumed first order kinetics. DCP and Eudragit® RS 100 also retarded release of SIM causing SIM release over 8 h after AML-B release from the optimized FDC tablet formulation. The HPLC retention times of AML-B and SIM were 2.10 and 15.52 min, respectively. Linearity for AML-B was 5.0-50 ng/mL and 0.01-2.0 µg/mL for SIM with percent recoveries of 92.85-101.53% and 94.51-117.75% for AML-B and SIM. AUC0-∞ of AML-B was increased 3 fold, while AUC0-∞ of SIM was decreased 2 fold. The tmax values for AML-B and SIM were 12 and 6 h, respectively. AML-B was absorbed without any lag time (tlag) while tlag was 6.33 ± 0.81 h for SIM, thus met the study objective. CONCLUSION: The pharmacokinetic study showed an immediate absorption of AML-B while that of SIM was withheld for 6 h, close to the desired delay time of 8 h.

Population pharmacokinetic modelling to quantify the magnitude of drug-drug interactions between amlodipine and antiretroviral drugs.

PURPOSE: Drug-drug interactions (DDIs) with antiretroviral drugs (ARVs) represent an important issue in elderly people living with HIV (PLWH). Amlodipine is a commonly prescribed antihypertensive drug metabolized by CYP3A4, thus predisposed to a risk of DDIs. Guidance on the management of DDIs is mostly based on theoretical considerations derived from coadministration with other CYP3A4 inhibitors. This study aimed at characterizing the magnitude of DDIs between amlodipine and ARV drugs in order to establish dosing recommendations. METHODS: A population pharmacokinetic analysis was developed using non-linear mixed effect modelling (NONMEM) and included 163 amlodipine concentrations from 55 PLWH. Various structural and error models were compared to characterize optimally the concentration-time profile of amlodipine. Demographic and clinical characteristics as well as comedications were tested as potential influential covariates. Model-based simulations were performed to compare amlodipine exposure (i.e. area under the curve, AUC) between coadministered ARV drugs. RESULTS: Amlodipine concentration-time profile was best described using a one-compartment model with first-order absorption and a lag-time. Amlodipine apparent clearance was influenced by both CYP3A4 inhibitors and efavirenz (CYP3A4 inducer). Model-based simulations revealed that amlodipine AUC increased by 96% when coadministered with CYP3A4 inhibitors, while efavirenz decreased drug exposure by 59%. CONCLUSION: Coadministered ARV drugs significantly impact amlodipine disposition in PLWH. Clinicians should adjust amlodipine dosage accordingly, by halving the dosage in PLWH receiving ARV with inhibitory properties (mainly ritonavir-boosted darunavir), whereas they should double amlodipine doses when coadministering it with efavirenz, under appropriate monitoring of clinical response and tolerance.

Pharmacokinetic drug-drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol.

LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug-drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open-label, single-sequence, 3-period, crossover design in healthy subjects. Blood samples were collected to determine the pharmacokinetic parameters of LCZ696 analytes (AHU377, LBQ657, and valsartan), HCTZ, amlodipine, or carvedilol (R[+]- and S[-]-carvedilol) for statistical analysis. When coadministered LCZ696 with HCTZ, the 90% CIs of the geometric mean ratios of AUCtau,ss of HCTZ and that of LBQ657 were within a 0.80-1.25 interval, whereas HCTZ Cmax,ss decreased by 26%, LBQ657 Cmax,ss increased by 19%, and the AUCtau,ss and Cmax,ss of valsartan increased by 14% and 16%, respectively. Pharmacokinetics of amlodipine, R(+)- and S(-)-carvedilol, or LBQ657 were not altered after coadministration of LCZ696 with amlodipine or carvedilol. Coadministration of LCZ696 400 mg once daily (qd) with HCTZ 25 mg qd, amlodipine 10 mg qd, or carvedilol 25 mg twice a day (bid) had no clinically relevant pharmacokinetic drug-drug interactions. LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies.

Antihypertensive response to combination of olmesartan and amlodipine does not depend on method and time of drug administration.

Fixed combinations of antihypertensive drugs have the potentiality to improve blood pressure (BP) control. However, when pharmacokinetic parameters of the two drugs are different, both method and time of administration of the two drugs may modify the antihypertensive response. In an open-label, single-blind, randomized study we compared antihypertensive effect of four administration schemes of a combination therapy of olmesartan and amlodipine in the same group of hypertensive patients, using ambulatory blood pressure monitoring (ABPM). The olmesartan + amlodipine combination has demonstrated to provide a good control of BP, with systolic and diastolic BP constantly below 130 and 85 mmHg over the 24 h. The simultaneous or separate administration of the 2 drugs fully overlapped, suggesting that the fixed combination and the separate administration induce a similar and sustained BP control.

[Modeling and simulation activities to design sampling scheme for population pharmacokinetic study on amlodipine].

Reasonable sampling scheme is the important basis for establishing reliable population pharmacokinetic model. It is an effective method for estimation of population pharmacokinetic parameters with sparse data to perform population pharmacokinetic analysis using the nonlinear mixed-effects models. We designed the sampling scheme for amlodipine based on D-optimal sampling strategy and Bayesian estimation method. First, optimized sample scenarios were designed using WinPOPT software according to the aim, dosage regimen and visit schedule of the clinical study protocol, and the amlodipine population model reported by Rohatagi et al. Second, we created a NONMEM-formatted dataset (n = 400) for each sample scenario via Monte Carlo simulation. Third, the estimation of amlodipine pharmacokinetic parameters (clearance (CL/F), volume (V/F) and Ka) was based on the simulation results. All modeling and simulation exercises were conducted with NONMEM version 7.2. Finally, the accuracy and precision of the estimated parameters were evaluated using the mean prediction error (MPE) and the mean absolute error (MAPE), respectively. Among the 6 schemes, schemes 6 and 3 have good accuracy and precision. MPE is 0.1% for scheme 6 and -0.6% for scheme 3, respectively. MAPE is 0.7% for both schemes. There is no significant difference in MPE and MAPE of volume among them. Therefore, we select scheme 3 as the final sample scenario because it has good accuracy and precision and less sample points. This research aims to provide scientific and effective sampling scheme for population pharmacokinetic (PK) study of amlodipine in patients with renal impairment and hypertension, provide a scientific method for an optimum design in clinical population PK/PD (pharmacodynamics) research.

Simultaneous determination of amlodipine and bisoprolol in rat plasma by a liquid chromatography/tandem mass spectrometry method and its application in pharmacokinetic study.

A sensitive, specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for the quantitative determination of amlodipine and bisoprolol, using clenbuterol as the internal standard (IS). The analytes and IS were isolated from 100µL plasma samples by a simple liquid-liquid extraction (LLE). Reverse-phase high performance liquid chromatography (RP-HPLC) separation was accomplished on a Diamonsil C(18) column (50mm×4.6mm, 5µm) with a mobile phase composed of methanol-water-formic acid (75:25:0.01, v/v/v) at a flow rate of 0.3mL/min. The method had a chromatographic total run time of 3min. Multiple reacting monitoring (MRM) transitions of m/z [M+H](+) 409.1→237.9 (amlodipine), m/z [M+H](+) 326.2→116.0 (bisoprolol) and m/z [M+H](+) 277.0→203.0 (clenbuterol, IS) were used to quantify amlodipine, bisoprolol and IS, respectively. The method was sensitive with a lower limit of quantitation (LLOQ) of 0.2ng/mL for both amlodipine and bisoprolol, and the linear range was 0.2-50ng/mL for both amlodipine and bisoprolol (r(2)>0.9961). All the validation data, such as accuracy, precision and inter-day repeatability, were within the required limits. The method was successfully applied to pharmacokinetic studies of amlodipine and bisoprolol in Sprague-Dawley (SD) rats.

Development and validation of a highly sensitive and robust LC-ESI-MS/MS method for simultaneous quantitation of simvastatin acid, amlodipine and valsartan in human plasma: application to a clinical pharmacokinetic study.

A high-throughput, simple, highly sensitive and specific LC-MS/MS method has been developed for simultaneous estimation of simvastatin acid (SA), amlodipine (AD) and valsartan (VS) with 500 microL of human plasma using deuterated simvastatin acid as an internal standard (IS). The API-4000 LC-MS/MS was operated under the multiple reaction-monitoring mode (MRM) using electrospray ionization. The assay procedure involved precipitation of SA, AD, VS and IS from plasma with acetonitrile. The total run time was 2.8 min and the elution of SA, AD, VS and IS occurred at 1.81, 1.12, 1.14 and 1.81 min, respectively; this was achieved with a mobile phase consisting of 0.02 M ammonium formate (pH 4.5):acetonitrile (20:80, v/v) at a flow rate of 0.50 mL/min on an X-Terra C18 column. A linear response function was established for the range of concentrations 0.5-50 ng/mL (r > 0.994) for VS and 0.2-50 ng/mL (r > 0.996) for SA and AD. The method validation parameters for all three analytes met the acceptance as per FDA guidelines. This novel method has been applied to human pharmacokinetic study.

Amlodipine/atorvastatin fixed-dose combination: a review of its use in the prevention of cardiovascular disease and in the treatment of hypertension and dyslipidemia.

Amlodipine/atorvastatin (Caduet) is a once-daily fixed-dose combination of the dihydropyridine calcium channel antagonist amlodipine and the HMG-CoA reductase inhibitor atorvastatin. In Europe, the combination is indicated for the prevention of cardiovascular events in hypertensive patients with three concomitant cardiovascular risk factors and, in the US, it is indicated for the management of hypertension and dyslipidemia in patients for whom treatment with both agents is appropriate. In clinical trials, the fixed-dose combination of amlodipine/atorvastatin effectively managed two important risk factors simultaneously in hypertensive patients at risk of cardiovascular disease or in those with concomitant hypertension and dyslipidemia. The combination is bioequivalent to amlodipine and atorvastatin given alone and does not modify the efficacy of either single agent. Amlodipine/atorvastatin is generally well tolerated, with a tolerability profile consistent with that of each single agent. Compared with the coadministration of each single agent, the convenience of single-pill amlodipine/atorvastatin has the potential to improve patient adherence and the management of cardiovascular risk in selected patients, thereby improving clinical outcomes.

Assessment of sex differences in pharmacokinetics and pharmacodynamics of amlodipine in a bioequivalence study.

AIMS: This study was conducted to assess the bioequivalence between two 10-mg amlodipine tablet formulations. As secondary objectives, sex-related differences and tolerability profile were evaluated. METHODS: Thirty-six healthy volunteers (18 males and 18 females; age 20-32 years, weight 49.5-98.0 kg) were included in a randomised crossover study. Subjects were administered a single 10-mg oral dose of each formulation separated by a 14-day washout period. Plasma amlodipine levels were determined by a high performance liquid chromatographic method with tandem mass spectrometry detection. RESULTS: All subjects completed the study and 90% confidence intervals for relevant pharmacokinetic parameters were within the ranges defined by European and US Regulatory Authorities: the geometric mean and the 90% confidence interval test/reference ratios calculated from log-transformed values were 104.54 (101.46-107.72%) for AUC(0-infinity) and 100.32 (97.41-103.33%) for Cmax. There were no serious or severe adverse events. The tolerability profile appeared to be comparable for the two products. On average, bioavailability of amlodipine was slightly higher in females than in males, but these differences could be explained by the lower body weight of women. There were no sex-related differences in drug clearance. Bioequivalence was also demonstrated within each gender group. Amlodipine treatment produced a slight decrease of systolic blood pressure and an increased in heart rate, which were more pronounced in women. The incidence of adverse events was similar in men and women. CONCLUSIONS: The two formulations were considered bioequivalent. Although there were no relevant gender-related differences in the pharmacokinetics of amlodipine, women reached higher amlodipine concentrations most likely because of their lower body weight, and therefore, the reported pharmacodynamic effects were higher within this gender group.

A comparative assessment of amlodipine and felodipine ER: pharmacokinetic and pharmacodynamic indices.

This study investigated potential therapeutic differences between Amlodipine 5 mg and Felodipine ER 10 mg in 12 normotensive/borderline hypertensive subjects by comparison of the plasma drug concentration-time profiles and the blood pressure and heart rate responses. There was significantly less trough-to-peak variability in plasma drug concentrations with amlodipine with a ratio of 67%, compared to 37% for felodipine. Correspondingly there was less variability with amlodipine in the blood pressure reductions across the dosage interval. Overall, amlodipine displayed a more consistent hypotensive effect across 24 hours and lower blood pressure values at trough, i.e. 24 hours post-dose.