Isradipine plasma pharmacokinetics and exposure-response in early Parkinson's disease.

OBJECTIVES: Isradipine is a dihydropyridine calcium channel inhibitor that has demonstrated concentration-dependent neuroprotective effects in animal models of Parkinson's disease (PD) but failed to show efficacy in a phase 3 clinical trial. The objectives of this study were to model the plasma pharmacokinetics of isradipine in study participants from the phase 3 trial; and, to investigate associations between drug exposure and longitudinal clinical outcome measures of PD progression. METHODS: Plasma samples from nearly all study participants randomized to immediate-release isradipine 5-mg twice daily (166 of 170) were collected for population pharmacokinetic modeling. Estimates of isradipine exposure included apparent oral clearance and area under the concentration-time curve. Isradipine exposure parameters were tested for correlations with 36-month changes in disease severity clinical assessment scores, and time-to-event analyses for initiation of antiparkinson therapy. RESULTS: Isradipine exposures did not correlate with the primary clinical outcome, changes in the antiparkinson therapy-adjusted Unified Parkinson's Disease Rating Scale parts I-III score over 36 months (Spearman rank correlation coefficient, rs : 0.09, P = 0.23). Cumulative levodopa equivalent dose at month 36 was weakly correlated with isradipine plasma clearance (rs : 0.18, P = 0.035). This correlation was sex dependent and significant in males, but not females. Those with higher isradipine exposure had decreased risk of needing antiparkinson treatment over 36 months compared with placebo (hazard ratio: 0.87, 95% CI: 0.78-0.98, P = 0.02). INTERPRETATION: In this clinical trial, higher isradipine plasma exposure did not affect clinical assessment measures of PD severity but modestly decreased cumulative levodopa equivalent dose and the time needed for antiparkinson treatment initiation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02168842.

Pharmacokinetic properties of isradipine after single-dose and multiple-dose oral administration in Chinese volunteers: a randomized, open-label, parallel-group phase I study.

Isradipine could be used for the treatment of high blood pressure or Parkinsonism, yet the study on pharmacokinetics (PK) of isradipine is lacking in the Chinese population. The current study aims to assess the dose proportionality, pharmacokinetics and gender effect of isradipine following oral single and multiple doses in Chinese subjects. A randomized, open-label, parallel-group trial was conducted in 30 healthy Chinese volunteers. Subjects randomly received a single dose of 2.5, 5 or 10 mg, and multiple doses (2.5 mg) of isradipine. Blood samples were collected pre-dose (0 h) and 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, 36 and 48 h post-dose. Isradipine was rapidly absorbed with the time to maximum concentration <1.27 h for all dosage groups. The maximum concentrations were 2.46, 5.34, 10.93 and 3.32 ng/mL and area under the concentration-time curve from time zero to the last time point (AUClast ) were 7.05, 12.58, 24.68 and 5.31 ng/ml · h for the 2.5, 5 and 10 mg single-dose and 2.5 mg multiple-dose groups, respectively. The half-life ranged from 5.76 to 7.94 h. The maximum concentration and AUC were found to increase linearly and dose-dependently for isradipine. No statistical gender differences were found. These findings indicated that the pharmacokinetic parameters of isradipine in Chinese population were dose-proportional and predictable over a range of 2.5-10 mg isradipine oral doses.

Physical properties and in vivo bioavailability in human volunteers of isradipine using controlled release matrix tablet containing self-emulsifying solid dispersion.

Poorly water-soluble drug with a short half-life such as isradipine (IDP) offer challenges in the controlled release formulation because of low dissolution rate and poor bioavailability. Self-emulsifying solid dispersions (SESD) of IDP consisted of surfactant and fatty acid in poloxamer 407 (POX 407) as a carrier and were manufactured by the melting method. Then, controlled release HPMC matrix tablet containing SESD were prepared via direct compression. The dissolution behaviors and in vivo bioavailability of controlled release matrix tablet in healthy human volunteers were investigated. The physical properties of solid dispersion were also examined using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM). It was shown that structure of IDP was amorphous in the solid dispersion. The dissolution rate of IDP from SESD was markedly enhanced because of increased solubility and wetting effect. Controlled release HPMC matrix tablets containing SESD released drug in a controlled manner and were stable during storage over 3 months at 40 °C/75% RH. Furthermore, the tablet containing 5mg IDP SESD showed significantly increased oral bioavailability and extended plasma concentration compared with the marketed 5 mg Dynacirc(®) capsule. A combined method of solid dispersion and controlled release technology could provide versatile dosage formulations containing IDP with poor water solubility and short half-life.

L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer's disease.

There is strong evidence that intracellular calcium dysregulation plays an important pathological role in Alzheimer's disease, and specifically that beta amyloid may induce increases in intracellular calcium and lead to neuronal cell dysfunction and death. Here we investigated the feasibility of modifying Alzheimer's pathology with the L-type voltage-gated calcium channel blockers verapamil, diltiazem, isradipine and nimodipine. All four compounds protected MC65 neuroblastoma cells from amyloid beta protein precursor C-terminal fragment (APP CTF)-induced neurotoxicity. Isradipine was the most potent blocker, preventing APP CTF neurotoxicity at nanomolar concentrations. Intracellular beta amyloid expression was associated with increased expression of Cav 1.2 calcium channels and increased intracellular calcium influx from the extracellular space. Despite the cytoprotection afforded by calcium channel blockers, amyloid beta oligomer formation was not suppressed. The mechanism of cell death in MC65 cells is appeared to be caspase-3 independent. With the goal of determining if there is sufficient experimental support to move forward with animal trials of isradipine, we determined its bioavailability in the triple transgenic mouse model of AD. Subcutaneous implantation of carrier-bound isradipine (3 µg/g/day) for 60 days resulted in nanomolar concentrations in both the plasma and brain. Taken together, our in vitro results support the theory that calcium blockers exert protective effects downstream of the effects of beta amyloid. Isradipine's neuroprotective effect at concentrations that are clinically relevant and achievable in vitro and in vivo suggests that this particular calcium blocking agent may have therapeutic value in the treatment of Alzheimer's disease.

Quantification of isradipine in human plasma using LC-MS/MS for pharmacokinetic and bioequivalence study.

A highly sensitive and rapid method for the analysis of isradipine in human plasma using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was developed. The procedure involves a simple liquid-liquid extraction of isradipine and amlodipine (IS, internal standard) with methyl-t-butyl ether after alkaline treatment and separation by RP-HPLC. Detection was performed by positive ion electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode, monitoring the transitions m/z 372.1-->m/z 312.2 and m/z 408.8-->m/z 237.9, for quantification of isradipine and IS, respectively. The standard calibration curves showed good linearity within the range of 10 to 5000 pg/mL (r(2)>or=0.9998). The lower limit of quantitation (LLOQ) was 10 pg/mL. The retention times of isradipine (0.81 min) and IS (0.65 min) suggested the potential for high throughput of the proposed method. In addition, no significant metabolic compounds were found to interfere with the analysis. This method offered good precision and accuracy and was successfully applied for the pharmacokinetic and bioequivalence studies of 5 mg of sustained-release isradipine in 24 healthy Korean volunteers.

[Toxicological analysis of selected 1,4-dihydropyridine calcium channel blockers in the diagnosis of intoxications]. / Analiza toksykologiczna wybranych pochodnych 1,4-dihydropirydyny w diagnostyce zatruc.

This study is aimed at evaluating effective techniques of qualitative and quantitative analysis of selected 1,4-dihydropyridine calcium channel blockers, useful both for thanatological diagnosis of intoxications as well as monitoring therapy. The studies took advantage of gas chromatography (GLC) and high performance liquid chromatography (HPLC). Isolation of studied compounds from biological material was performed using classical and solid phase extraction procedures (SPE) such as Bond Elut LRC (Varian), Abselut Nexus (Varian), STRATA C - 18 E (Phenomenex). The program included analysis of nine of the most frequently prescribed derivatives: nifedipine, felodipine, amlodipine, nicardipine, nimodypine, nilvadipine, nitrendipine, nisoldipine, isradipine.

Voltammetric determination of isradipine in dosage forms and spiked human plasma and urine.

The voltammetric behavior of isradipine was studied using direct current (DC(t)), differential-pulse (DPP) and alternating current (AC(t)) polarography. Isradipine exhibited well-defined cathodic waves over the whole pH range in Britton-Robinson buffer (BRb). At pH 5, the analytical pH, the diffusion-current constant (Id) was 8.27+/-0.52. The current-concentration plots were rectilinear over the range 1-20 and 0.1-18 microg/ml using the DC(t) and DPP modes, respectively, with minimum detectability of 0.01 microg/ml (2.7 x 10(-8) M) using the latter technique. The current has been characterized as being diffusion-controlled, although adsorption phenomenon played a limited role in the electrode process. The proposed method was applied to commercial tablets and capsules. The percentage recoveries were in good agreement with those given by the manufacturer. The method was further extended to the in-vitro determination of the drug in spiked human urine and plasma, the percentage recoveries were (n = 4) 100.12+/-1.42 and 103.88+/-5.13, respectively. The number of electrons involved in the reduction process was accomplished and a proposal of the electrode reaction was presented.

Life-threatening isradipine poisoning in a child.

Calcium channel blockers as a group are responsible for significant morbidity and mortality with toxic exposures. Isradipine, a cardioselective dihydropyridine calcium channel blocker, rarely has been implicated, with only two reports in the literature of significant toxic reactions, one in an adult and another in a child. To our knowledge, we describe the first case of life-threatening isradipine poisoning in a child and provide documentation of serum drug levels. On arrival at the hospital, a 5-year-old girl had abdominal distention and bradycardia that rapidly progressed to asystole. She received 73 minutes of cardiopulmonary resuscitation and transvenous cardiac pacing and survived with an intact neurologic recovery. Serum concentrations of isradipine were 30-100 times those found with therapeutic use.

Redox properties of isradipine and its electrochemical detection in the HPLC determination of the compound in human serum.

The electrochemical behaviour of isradipine in a mixed solution of Britton-Robinson buffer (pH 11.8):acetonitrile:methanol (6:3:1, v/v) was studied by cyclic voltammetry and spectroelectrochemistry using an optically transparent thin layer electrode of carbon cloth. The cyclic voltammogram showed several peaks whose shape and potentials depended on the pH. The peak at 330 nm, corresponding to the absorbance of the dihydropyridine ring, disappeared after electrolysis at a potential that was more positive than the oxidation peak. The oxidation peak corresponds to the oxidation of the dihydropyridine ring. Peak height at pH 11.8 was proportional to isradipine concentration. On the basis of the redox properties of isradipine, HPLC was conducted applying electrochemical detection on a polybutadiene coated alumina column using an alkaline mobile phase. The method was applied for the determination of isradipine content in human serum. A good linear relationship between isradipine concentration and peak height was found in the concentration range of 2-200 ng/mL with a correlation coefficient of 0.9924. The detection limit was 0.5 ng/mL. The within-day and day-to-day variation were examined for control human serum and percentage relative standard deviation ranged from 0.5 to 6.7. Interference from many other coadministered drugs was studied in the specified experimental conditions. Photo and heat stabilities of the compound were also studied.

In vivo specific binding characteristics and pharmacokinetics of a 1,4-dihydropyridine calcium channel antagonist in the senescent mouse brain.

PURPOSE: To characterize the in vivo specific binding and pharmacokinetics of a 1,4-dihydropyridine (DHP) calcium channel antagonist, PN 200-110, in the senescent brain, using senescence-accelerated prone mice (SAMP8) and senescence-resistant mice (SAMR1). METHODS: Blood, brain, and heart samples were taken periodically from SAMR1 and SAMP8 following intravenous injection of (+)-[3H]PN 200-110, and the concentration of (+)-[3H]PN 200-110 in the plasma and tissues was determined. In addition, the in vivo specific binding of (+)-[3H]PN 200-110 in the brains of SAMRI and SAMP8 was measured periodically after intravenous injection of the radioligand. RESULTS: There was very little significant difference between SAMR1 and SAMP8 in terms of the half-life (t(1/2)), total body clearance (CL(tot)), steady-state volume of distribution (Vd(ss)). and AUC for the plasma concentration of (+)-[3H]PN 200-110 after intravenous injection of the radioligand. The brain concentration (AUCbrain) for (+)-[3H]PN 200-110 and the brain/plasma AUC ratio (AUCbrain/AUCplasma) were significantly lower in SAMP8 than in SAMR1, and the heart concentration (AUCheart) and the heart/plasma AUC ratio (AUCheart/AUCplasma) were similar in both strains. Also, the brain/plasma unbound AUC ratio (AUCbrain/AUCplasma-free) for (+)-[3H]PN 200-110 was significantly lower in SAMP8 than in SAMRI. The in vivo specific binding (AUCspecific binding, maximal number of binding sites: Bmax) of (+)-[3H]PN 200-110 was significantly lower in brain particulate fractions of SAMP8 than SAMR1. CONCLUSIONS: The concentration and in vivo specific binding of (+)-[3H]PN 200-110 was significantly reduced in the senescent brain. The simultaneous analysis of the concentrations of centrally acting drugs and the in vivo specific binding in the brain in relation to their pharmacokinetics may be valuable in evaluating their CNS effects.

Bioavailability and pharmacokinetics of isradipine after oral and intravenous administration: half-life shorter than expected?

Isradipine is a calcium channel-blocking agent of the dihydropyridine type, used in the treatment of hypertension. A terminal half-life of 8-9 hr has been reported, in several pharmacokinetic studies after oral administration of isradipine. In a yet unpublished study a much shorter half-life was observed, and the present trial was therefore conducted in order to estimate the half-life after intravenous administration of isradipine. The bioavailability was estimated as well. In a randomised cross-over design ten healthy young volunteers were given either isradipine orally or an intravenous infusion. The two study periods were separated by at least 3 days. Blood samples for measurement of isradipine concentration were collected for 10-12 hr after administration and half-life and bioavailability were estimated. Mean terminal half-life after intravenous administration was calculated to be 2.8 hr, and the bioavailability to be 0.28. None of the 10 subjects suffered from side effects. In the present intravenous study the half-life of isradipine seems to be of much shorter than demonstrated in previous oral studies.

Enantioselective determination of isradipine in human serum using chiral stationary phase liquid chromatography and gas chromatography with nitrogen selective detection.

rac-Isradipine is a dihydropyridine type calcium antagonist. Its calcium entry blocking effect is due primarily to the (+)-(S)-enantiomer. This study describes a sensitive enantioselective method for the determination of isradipine in human serum. Following alkaline extraction into hexane, the enantiomers of isradipine are separated quantitatively by high-performance liquid chromatography on a Chiralcel OJ column at 39 degrees C. The collected fractions were evaporated and assayed using capillary gas chromatography on a HP 50+ column with nitrogen selective detection. Using 2.0 ml of serum, 0.7 nmol/1 (0.26 ng/ml) of each enantiomer could be determined with acceptable precision. The method has successfully been used to measure (+)-(S)- and (-)-(R)-isradipine concentrations in samples from volunteers after intravenous and oral administration of isradipine.

Pharmacokinetics and dynamic response of plain and slow release isradipine formulations in moderately hypertensive patients.

The pharmacokinetic variables and antihypertensive effect of the calcium antagonist isradipine, were investigated in 30 hypertensive patients. Isradipine was given orally in parallel group design in plain and slow release formulations in doses of 2.5 mg twice daily and 5.0 mg once daily, respectively. Isradipine concentration in serum was measured by a sensitive RIA method after the first dose and after 6 weeks of treatment. The pharmacokinetics and concentration/effect relationship after the first dose and after 6 weeks of treatment were compared. No differences in pharmacokinetics were observed between single and multiple dosing. Data were in accordance with results from studies in healthy volunteers. Rate, but not extent of bioavailability differs between the two isradipine formulations. Antihypertensive efficacy of the two formulations was similar (16/11 and 19/15 mmHg), and a significant time dependent increase in Emax from 10/3 mmHg to 23/14 mmHg after 6 weeks of treatment was observed.

Bioequivalence of a slow-release and a non-retard formulation of isradipine.

Pharmacokinetic studies were carried out in 48 healthy male volunteers to determine the pharmacokinetic properties of a new modified-release formulation of isradipine (SRO) and to compare these with the pharmacokinetic properties of the nonretard form of isradipine (NR). Studies were carried out in the fasting state and also following a light meal. The time required to reach maximum plasma concentration (tmax) was extended from approximately 1.5 h with NR to 5 to 7 h with SRO, and the maximum plasma concentration [Cp(tmax)] was reduced by around 50%. The bioavailability of SRO was increased by less than 20% compared with the same daily dose given as NR, indicating that the two forms are bioequivalent and that no adjustment in the total daily dose of isradipine is necessary when switching from one form to the other. Administration with a light meal altered the pharmacokinetic parameters by less than 20% compared with administration without food.