Fluctuations In Plasma Concentrations Research Articles

Dexmethylphenidate Extended Release

Dexmethylphenidate extended release (XR) is an orally administered, bimodal release, capsule formulation of the active d-enantiomer of methylphenidate (MPH), which inhibits dopamine and norepinephrine (noradrenaline) reuptake to increase their concentration in the extraneuronal space. A single dose of dexmethylphenidate XR mimics the pharmacokinetic profile of two doses of dexmethylphenidate immediate-release formulation administered 4 hours apart, albeit with less fluctuation in plasma concentration. Once-daily dexmethylphenidate XR was more effective than placebo in reducing attention-deficit hyperactivity disorder (ADHD) symptom scores in children, adolescents and adults with ADHD in four randomised, double-blind, placebo-controlled trials of up to 7 weeks' duration. In crossover trials in children (aged 6-12 years), dexmethylphenidate XR 20 mg/day reduced mean ADHD symptom scores 1 hour after administration (by 43% in one trial) and was significantly better than placebo for up to 12 hours. Dexmethylphenidate XR 5-30 mg/day reduced mean ADHD symptom scores by 49%, while scores declined by 16% with placebo in a 7-week trial in children and adolescents (aged 6-17 years). Dexmethylphenidate XR 20, 30 or 40 mg/day reduced ADHD symptom scores by 36-46% versus a 21% reduction with placebo in a 5-week trial in adults (aged 18-60 years). Dexmethylphenidate XR was generally well tolerated in children, adolescents and adults with ADHD, with an adverse-event profile typical of MPH.

The metamorphosis of hydromorphone

Hydromorphone, one of the oldest and most potent of opioids, is an effective alternative to morphine. With a variety of routes of administration, it has an efficacy similar to that of morphine. The FDA has recently approved the first commercially available extended-release formulation, a once-daily hydromorphone for the management of moderate to severe pain in opioid tolerant individuals with an anticipated extended period of use. The formulation exhibits less peak-to-trough fluctuation in plasma concentration, while providing analgesia statistically indistinguishable from its immediate-release counterpart. The manufacturer and the FDA have articulated a plan to minimize unskillful prescribing and abuse/diversion through education, supply-chain integrity, and surveillance. It is anticipated that Palladone will be a valuable addition to the limited armamentarium of extended-release opioids.

Temperature effects on trimethylamine oxide accumulation and the relationship between plasma concentration and tissue levels in smelt (Osmerus mordax)

Rainbow smelt (Osmerus mordax) were maintained in a long term acclimation study to elucidate temperature effects on the accumulation of trimethylamine oxide (TMAO) and to determine if the activity of trimethylamine oxidase (TMAoxi) plays a role in modulating the seasonally variable levels of TMAO. In the same experiment, the TMAO content was determined for several tissues at varying plasma TMAO concentrations. TMAO accumulation begins at 5-7 degrees C, well above that which might be normally associated with an antifreeze response. The plasma concentration reached a plateau of 20 mM as temperatures reached 0 degrees C. Plasma TMAO concentration drops to pre-accumulation levels, less than 5 mM, when fish are held at elevated temperature (8-11 degrees C) and increases when fish are chilled below ambient seawater temperatures. However, despite temperatures near or below 0 degrees C, plasma TMAO decreases after the winter season. Changes in TMAoxi activity do not correlate with TMAO levels, suggesting that the activity of this enzyme does not play a key role in regulating TMAO concentrations in smelt. For the first time in any teleost fish, tissue TMAO contents in liver, kidney, brain, and intestine were found to strongly correlate with plasma TMAO concentrations. For these tissues, the intracellular and extracellular concentration of TMAO appears to be approximately equal. Conversely, the heart and white muscle accumulate TMAO, and in the case of white muscle, intracellular concentration is maintained at a constant level of approximately 35 mmol/kg, despite fluctuating plasma concentrations over a range from 0 to over 25 mM.

Antimicrobial Therapy in Critically Ill Patients

Antimicrobials are among the most important and commonly prescribed drugs in the management of critically ill patients. Selecting the appropriate antimicrobial at the commencement of therapy, both in terms of spectrum of activity and dose and frequency of administration according to concentration or time dependency, is mandatory in this setting. Despite appropriate standard dosage regimens, failure of the antimicrobial treatment may occur because of the inability of the antimicrobial to achieve adequate concentrations at the infection site through alterations in its pharmacokinetics due to underlying pathophysiological conditions. According to the intrinsic chemicophysical properties of antimicrobials, hydrophilic antimicrobials (beta-lactams, aminoglycosides, glycopeptides) have to be considered at much higher risk of inter- and intraindividual pharmacokinetic variations than lipophilic antimicrobials (macrolides, fluoroquinolones, tetracyclines, chloramphenicol, rifampicin [rifampin]) in critically ill patients, with significant frequent fluctuations of plasma concentrations that may require significant dosage adjustments. For example, underexposure may occur because of increased volume of distribution (as a result of oedema in sepsis and trauma, pleural effusion, ascites, mediastinitis, fluid therapy or indwelling post-surgical drainage) and/or enhanced renal clearance (as a result of burns, drug abuse, hyperdynamic conditions during sepsis, acute leukaemia or use of haemodynamically active drugs). On the other hand, overexposure may occur because of a drop in renal clearance caused by renal impairment. Care with all these factors whenever choosing an antimicrobial may substantially improve the outcome of antimicrobial therapy in critically ill patients. However, since these situations may often coexist in the same patient and pharmacokinetic variability may be unpredictable, the antimicrobial policy may further benefit from real-time application of therapeutic drug monitoring, since this practice, by tailoring exposure to the individual patient, may consequently be helpful both in improving the outcome of antimicrobial therapy and in containing the spread of resistance in the hospital setting.

Phase I trial of the oral farnesyl protein transferase inhibitor lonafarnib (SCH66336): A Pediatric Brain Tumor Consortium (PBTC) study

1517 Background: Children with recurrent or progressive central nervous system (CNS) tumors after optimal up-front therapy have a poor prognosis. Ras mutations or over-expression have been identified in both adult and pediatric brain tumors. Pre-clinical studies have demonstrated that both ras mutant and non-mutated tumors that signal through this pathway can be effectively inhibited by farnesyl transferase inhibitors. We now report the results of the first phase I dose escalation trial of lonafarnib (Sarasar) administered orally twice daily to children with recurrent or progressive, poor prognosis CNS tumors. Methods: The primary objective of this study was to assess the dose-limiting toxicities (DLTs) and maximally tolerated dose (MTD) of Sarasar. Additionally, the multiple dose pharmacokinetics of Sarasar was evaluated in patients both receiving or not receiving steroids. A preliminary assessment of activity was also performed. The dose of Sarasar has ranged from 70 mg/m2 (dose level 0) to 90, 115, 150 and is currently at 200 mg/m2/dose BID given by mouth without planned interruption. Evaluation for DLT was performed during the first 4 wks of therapy. Results: Thirty-nine children have been evaluated for this study to date (22 male/17 female), median age 13.4 years (range 3.9–19.5), with the following tumor types: high-grade glioma (17), brain stem glioma (6), medulloblastoma (3), PNET (4), ependymoma (2), low-grade glioma (3), meningioma (3), and gliomatosis cerebri (1). Therapy has been well tolerated and dose escalation continues. To date, the multiple dose PK have been determined in 9 patients. Sarasar is absorbed and eliminated slowly after oral administration with food. Median Tmax was 4 hr and there was minimal fluctuation in plasma concentrations. Pre-dose steady state concentrations were 26 to 100% of Cmax values. Conclusions: This dose escalation of oral Sarasar in children with CNS tumors continues to accrue patients at the 200mg/m2/dose given BID by oral administration. Full details of the dose-limiting and maximally-tolerated dose, pharmacokinetics and preliminary discussion of activity will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough Schering-Plough Schering-Plough Schering-Plough Schering-Plough

Avinza® – 24-h sustained-release oral morphine therapy

Avinza® is a once-daily, extended-release oral morphine preparation. It has a pharmacokinetic profile that exhibits less peak-to-trough fluctuations in plasma concentration whilst providing analgesia statistically identical to that produced by MS Contin® (controlled-release morphine sulfate), Oxycontin® (oxycodone HCl controlled-release) and six doses of oral morphine sulfate administered every 4 h. Avinza improves quality of sleep by several measures but interestingly gives the best sleep improvement when given in the morning rather than at night. It causes the same side effects of other opioids: constipation, nausea, vomiting, somnolence and mood swings. Doses of 30 – 60 mg/day have been shown to be well tolerated by patients with osteoarthritis (even in the elderly), who have failed other medications.

Avinza� ? 24-h sustained-release oral morphine therapy

Avinza® is a once-daily, extended-release oral morphine preparation. It has a pharmacokinetic profile that exhibits less peak-to-trough fluctuations in plasma concentration whilst providing analgesia statistically identical to that produced by MS Contin® (controlled-release morphine sulfate), Oxycontin® (oxycodone HCl controlled-release) and six doses of oral morphine sulfate administered every 4 h. Avinza improves quality of sleep by several measures but interestingly gives the best sleep improvement when given in the morning rather than at night. It causes the same side effects of other opioids: constipation, nausea, vomiting, somnolence and mood swings. Doses of 30 – 60 mg/day have been shown to be well tolerated by patients with osteoarthritis (even in the elderly), who have failed other medications.

Bioavailability of a Divalproex Extended-Release Formulation versus???the???Conventional Divalproex Formulation in Adult Patients Receiving Enzyme-Inducing Antiepileptic Drugs

To compare the bioavailability of divalproex extended release (divalproex-ER) given once daily relative to the conventional divalproex formulation given once every 8 hours, using various divalproex-ER doses that are 8-20% greater than the corresponding divalproex total daily doses. This multiple-dose, fasting, randomised, two-period, crossover design study in 76 subjects with epilepsy taking a concomitant enzyme-inducing antiepileptic drug compared the bioavailability of divalproex once-every-8-hours regimens with 8-20% higher daily dose divalproex-ER once-daily regimens. The 8-20% higher divalproex-ER once-daily-dose regimens were equivalent, with respect to exposure (area under the concentration-time curve; 1551 vs 1539 mg . h/L), to the corresponding total daily divalproex dose regimens. The divalproex-ER maximum concentration central value was significantly lower (83.3 vs 92.6 mg/L), and the minimum concentration mean was not significantly different (45.8 vs 44.8 mg/L) from the corresponding values for the divalproex regimen. The peak-to-trough fluctuation in plasma concentrations was significantly lower for once-daily divalproex-ER (64%) compared with once-every-8-hours divalproex (79%). The size of the divalproex dose and the presence of a concomitant enzyme-inducing antiepileptic drug did not have a statistically significant effect on divalproex-ER/divalproex relative bioavailability. No adverse event occurred in more than 5% of subjects on either treatment; all were mild or moderate in severity with none resulting in discontinuation. Both tested formulations were well tolerated by the subjects. This study demonstrated that patients with epilepsy taking divalproex may switch to 8-20% higher doses of divalproex-ER and have equivalent valproic acid exposure, lower fluctuation in valproic acid concentrations, and similar tolerability.

Pharmacology of systemic analgesics

Systemic administration of analgesic drugs is still the most widely used method for providing pain relief in acute painful situations. Opioids may be selected on the basis of their physicochemical characteristics and their diffusion index to the brain. But in clinical practice, their very steep concentration–analgesic effect relationship remains a critical aspect of opioid therapy. Thus, small fluctuations in plasma concentrations of opioids may lead to profound fluctuations in analgesic effect when their plasma and effect-site concentrations are near the minimum effective analgesic concentration (MEAC). Combining drugs acting on different mechanisms of nociceptive modulation offers benefits from additive/synergistic effects and will decrease the incidence of their adverse effects. Evidence-based reviews showed that effective pain relief using non-opioid analgesics relied on paracetamol supplemented with non-steroidal anti-inflammatory drugs (NSAIDs). The role of COX-2 selective inhibitors (CSIs) in acute pain relief still requires further evaluation. NSAIDs, CSIs and paracetamol share the property of morphine sparing in situations of severe (post-operative) pain. CSIs may be beneficial in patients in whom post-operative bleeding is a major surgical risk as the effects of NSAIDs on coagulation may last for days. Finally, low-dose ketamine infusions remain a worthwhile addition to opioid therapy. Analgesic concentrations of ketamine are 1/5th to 1/10th the anaesthetic concentration and exert significant inhibition on N–methyl–d-aspartate (NMDA) receptor activation.

Controlled delivery of metoclopramide using an injectable semi-solid poly(ortho ester) for veterinary application

In animal health care, current therapeutic regimens for gastrointestinal disorders require repeated oral or parenteral dosage forms of anti-emetic agents. However, fluctuations of plasma concentrations produce severe side effects. The aim of this work is to develop a subcutaneous and biodegradable controlled release system containing metoclopramide (MTC). Semi-solid poly(ortho ester)s (POE) prepared by a transesterification reaction between trimethyl orthoacetate and 1,2,6,-hexanetriol were investigated as injectable bioerodible polymers for the controlled release of MTC. MTC is present in the polymeric matrix as a solubilised form and it is released rapidly from the POE by erosion and diffusion because of its acidic character and its high hydrosolubility. If a manual injection is desired, only low molecular weight can be used. However, low molecular weight POEs release the drug rapidly. In order to extend polymer lifetime and decrease drug release rate, a sparingly water-soluble base Mg(OH) 2 was incorporated to the formulation. It was possible to produce low molecular weight POE that can be manually injected and releasing MTC over a period of several days.

Estimate the time varying brain receptor occupancy in PET imaging experiments using non-linear fixed and mixed effect modeling approach

Positron-Emission Tomography (PET) is an imaging technology currently used in drug development as a non-invasive measure of drug distribution and interaction with biochemical target system. The level of receptor occupancy achieved by a compound can be estimated by comparing time-activity measurements in an experiment done using tracer alone with the activity measured when the tracer is given following administration of unlabelled compound. The effective use of this surrogate marker as an enabling tool for drug development requires the definition of a model linking the brain receptor occupancy with the fluctuation of plasma concentrations. However, the predictive performance of such a model is strongly related to the precision on the estimate of receptor occupancy evaluated in PET scans collected at different times following drug treatment. Several methods have been proposed for the analysis and the quantification of the ligand-receptor interactions investigated from PET data. The aim of the present study is to evaluate alternative parameter estimation strategies based on the use of non-linear mixed effect models allowing to account for intra and inter-subject variability on the time-activity and for covariates potentially explaining this variability. A comparison of the different modeling approaches is presented using real data. The results of this comparison indicates that the mixed effect approach with a primary model partitioning the variance in term of Inter-Individual Variability (IIV) and Inter-Occasion Variability (IOV) and a second stage model relating the changes on binding potential to the dose of unlabelled drug is definitely the preferred approach.

Single- and Multiple-Dose Pharmacokinetics and Tolerability of Gepirone Extended-Release

To determine the single- and multiple-dose pharmacokinetic profile of gepirone extended-release (ER) in healthy individuals. The single- and multiple-dose pharmacokinetics of gepirone-ER were investigated in three randomised, placebo-controlled studies of 115 healthy subjects. Dosages ranged from 10 to 75 mg/day for 6 days (study 1), 20 mg/day for 7 days (study 2), and 120 mg/day for 7 days (study 3). Blood samples were obtained to measure plasma levels of gepirone and the l-pyrimidinyl-(2-pipera-zine) [1-PP] metabolite prior to the first dose and other intervals on the first and last treatment days. Pharmacokinetic parameters included peak plasma level (Cmax), time to peak plasma level (tmax), and area under the concentration-time curve (AUC). In single-dose studies, peak gepirone-ER plasma concentrations were reached in approximately 4 to 5 hours and slowly declined over the next 20 hours. Steady-state plasma gepirone concentrations were reached by day 2 during multiple-dose studies; Cmax, minimum trough plasma concentration (Cmin) and AUC were dose proportional. Greater fluctuations in plasma concentrations were observed with gepirone solution than with gepirone-ER. The AUC for gepirone-ER was approximately 80% of that for gepirone solution. A similar pharmaco-kinetic profile was observed for the 1-PP metabolite. Gepirone-ER was generally well tolerated at all doses in all age groups except for 120 mg/day. The incidence of adverse events, including headache, dizziness and nausea, tended to be higher in gepirone-ER than in placebo recipients. Gepirone and 1-PP exhibited linear pharmacokinetic profiles. Peak/trough fluctuations in plasma gepirone concentrations were reduced by gepirone-ER, while total exposure to drug (AUC) was maintained. Overall, gepirone-ER was well tolerated. As a result of lower peak plasma levels, gepirone-ER may be expected to reduce the incidence of adverse events compared with gepirone immediate-release and thus has the potential to improve response.

Study of diurnal fluctuations of plasma methoxyamines in healthy volunteers.

We studied the diurnal fluctuations of plasma concentrations of methoxyamines (metanephrine and normetanephrine) and of their parent amines (epinephrine and norepinephrine) in normotensive subjects. Serial blood sampling at 09.00 h, 11.00 h, 12.00 h, 14.00 h, 16.00 h, 18.00 h and 20.00 h in 28 healthy volunteers at rest. Determination of plasma concentrations of free catecholamines and total methoxyamines (free and sulpho-conjugates) was carried out by high-performance liquid chromatography with electrochemical detection. Mean (+/- SD) plasma concentrations of total metanephrine (MN) and normetanephrine (NMN) were 4.31 +/- 1.73 nmol/l (range: 0.96-9.3 nmol/l) and 8.13 +/- 2.54 nmol/l (range: 3.14-17.0 nmol/l), respectively. The NMN/MN ratio ranged between 0.8 and 7.8 (mean +/- SD 2.1 +/- 1.0). Mean plasma concentrations of free epinephrine and norepinephrine were 0.21 +/- 0.12 nmol/l (range: 0.06-1.39 nmol/l) and 1.61 +/- 0.62 nmol/l (range: 0.47-4.01 nmol/l), respectively. Despite marked intraindividual fluctuations, mean methoxyamine and catecholamine levels remained constant over the entire duration of the experiment. The absence of fluctuations of plasma levels of total methoxyamines suggests that their measurement could be carried out at any time within the diurnal time frame. Further investigations, however, remain necessary to validate these findings in patients with hypertension and/or pheochromocytoma, and to explain the ever important intraindividual variation in plasma concentrations of methoxyamines and of their parent compounds.

Selenium, zinc and copper plasma levels in intrahepatic cholestasis of pregnancy, in normal pregnancies and in healthy individuals, in Chile

Background/Aims: Low blood Se levels have been previously shown in normal pregnancies (third trimester) and significantly lower levels in patients with intrahepatic cholestasis of pregnancy (ICP), in Finland and in Chile, suggesting that a low or marginal dietary availability of Se may contribute to the pathogenesis of this disease. The aim of this study was to investigate whether a temporal change in plasma concentration of Se, and seasonal fluctuations in plasma concentrations of Se, Zn and Cu, could coincide with changes in the prevalence of ICP. Methods: A cross-sectional cohort study was done including 21 ICP patients, 98 women in the third trimester of a normal pregnancy, 29 non-pregnant women, and also 13 individuals (seven non-pregnant women and six men) who had been studied 9 years before. Plasma Se, Zn and Cu were measured by atomic spectroscopy. Plasma Se levels in the present study were compared to the results obtained 5 to 7 years before, employing identical methodology in similar population samples. Results: Plasma Se concentrations in non-pregnant women were higher than in the previous study: 1.43±0.34 μmol/l vs 0.85±0.13; p<0.001. In comparison to non-pregnant women, normal pregnancies near term had lower plasma levels of Se: 1.08±0.25 μmol/l; p<0.01, and Zn: 17.90±3.61 μmol/l vs 19.71±3.21; p<0.05, but higher plasma levels of Cu: 34.35±7.12 μmol/l vs 20.62±3.34; p<0.01. In normal pregnancies, plasma Se concentration was significantly higher in summer (1.34±0.19 μmol/l) than in the other seasons, while Zn and Cu diminished. Similar to previous studies, ICP patients had significantly lower Se plasma levels than normal pregnancies: 0.94±0.12 μmol/l, p<0.05, and Cu levels were significantly higher: 50.80±7.02 μmol/l, p<0.01. Cu plasma levels correlated with the biochemical severity of the disease. Zn did not change in ICP. Conclusions: The present study shows that the decrease in the prevalence of ICP in Chile during the last decade coincides with an increase in plasma Se levels. Its lower incidence during summer coincides with a higher plasma Se concentration in summer than in other seasons, as observed in normal pregnancies.

Transport of Glutamate and Other Amino Acids at the Blood-Brain Barrier

In most regions of the brain, the uptake of glutamate and other anionic excitatory amino acids from the circulation is limited by the blood-brain barrier (BBB). In most animals, the BBB is formed by the brain vascular endothelium, which contains cells that are joined by multiple bands of tight junctions. These junctions effectively close off diffusion through intercellular pores; as a result, most solutes cross the BBB either by diffusing across the lipoid endothelial cell membranes or by being transported across by specific carriers. Glutamate transport at the BBB has been studied by both in vitro cell uptake assays and in vivo perfusion methods. The results demonstrate that at physiologic plasma concentrations, glutamate flux from plasma into brain is mediated by a high affinity transport system at the BBB. Efflux from brain back into plasma appears to be driven in large part by a sodium-dependent active transport system at the capillary abluminal membrane. Glutamate concentration in brain interstitial fluid is only a fraction of that of plasma and is maintained fairly independently of small fluctuations in plasma concentration. Restricted brain passage is also observed for several excitatory glutamate analogs, including domoic acid and kynurenic acid. In summary, the BBB is one component of a regulatory system that helps maintain brain interstitial fluid glutamate concentration independently of the circulation.

COMT inhibition: a new treatment strategy for Parkinson's disease.

During the initial stages of Parkinson's disease, treatment with levodopa plus a decarboxylase inhibitor (carbidopa or benserazide) provides adequate control of symptoms. However, as the disease progresses, the clinical response to treatment often begins to fluctuate, becoming increasingly correlated with fluctuations in plasma concentrations of levodopa-the "wearing-off" phenomenon. Many strategies have attempted, with various degrees of success, to increase the availability of levodopa and its active metabolites, thus reducing these fluctuations in response. This review focuses on the role of the new catechol O-methyltransferase (COMT) inhibitors tolcapone and entacapone as adjuncts to levodopa therapy. These agents act effectively and safely to increase the amount of levodopa that is available to enter the brain by extending the half-life of levodopa, resulting in more stable levels in the plasma and prolonging "on" time.

Efficacy and pharmacokinetics of site-specific cefazolin delivery using biodegradable implants in the prevention of post-operative wound infections.

The study objective was to evaluate the efficacy and pharmacokinetics of cefazolin delivered locally as a glyceryl monostearate (GMS) based biocompatible implant for prevention of post-operative wound infection in Sprague Dawley rats subcutaneously inoculated with Staphylococcus aureus. For the efficacy and pharmacokinetic studies, 18 rats were subcutaneously inoculated with 4.5 x 10(7) CFU of S. aureus on the dorsum (6 per rat), and randomly assigned into three group of 6 rats each: (1) the control group, in which rats did not receive antibiotics, (2) the intermittent i.m. treatment group, in which rats received i.m. injections of 10 mg/kg cefazolin every 4 hr (total of 180 mg/kg in 3 days), and (3) the implant treatment group, in which rats were implanted subcutaneously with four Cefazolin-GMS implants in the vicinity of the inoculations. The implants were designed to deliver 180 mg/kg cefazolin over a 3 day period. For efficacy evaluation, the rats were euthanized one week post-inoculation and abscess count, weight and size were determined. Rats in the control group had developed 21 abscesses out of the 36 inoculations, indicating validity of the infection model. The local delivery of cefazolin resulted in complete eradication of the infection, since no abscesses formed in the rats in the implant group. In the IM treatment group, only one abscess was formed and no significant difference in efficacy between the two treatment groups was observed. The GMS implants sustained the release of cefazolin for a period of three days with only 3-fold fluctuations in plasma concentration (5.5-17.5 micrograms/ml). However, plasma concentrations after the intermittent IM administration of cefazolin fluctuated 110-fold between 44-0.4 micrograms/ml every 4 hr. The release rate of cefazolin from the implants was nearly zero order for the entire duration. Bioerosion of the implants was determined by examining the condition of the implants six weeks post-implantation. Two of the 12 implants had completely disappeared and the remaining implants were in a pasty form and had lost 20-80% of their weight. Absence of irritation or inflammation around the implants indicated biocompatibility of the GMS implants. Implantable system that provided a prolonged delivery of cefazolin was found to be effective against S. aureus infection, and demonstrated suitable pharmacokinetics and biocompatibility with significant bioerosion.

Clinical pharmacokinetics of nisoldipine coat-core.

Nisoldipine, a calcium antagonist of the dihydropyridine type, is the active ingredient of the controlled release nisoldipine coat-core (CC) formulation. In humans, the absorption from nisoldipine CC occurs across the entire gastrointestinal tract with an increase in bioavailability in the colon because of the lower concentrations of metabolising enzymes in the distal gut wall. Although nisoldipine is almost completely absorbed, its absolute bioavailability from the CC tablet is only 5.5%, as a result of significant first-pass metabolism in the gut and liver. Nisoldipine is a high-clearance drug with substantial interindividual and relatively lower intraindividual variability in pharmacokinetics, dependent on liver blood flow. Nisoldipine is highly (> 99%) protein bound. Its elimination is almost exclusively via the metabolic route and renal excretion of metabolites dominates over excretion in the faeces. Although nisoldipine is administered as a racemic mixture, its plasma concentrations are almost entirely caused by the eutomer as a result of highly stereoselective intrinsic clearance. Nisoldipine CC demonstrates linear pharmacokinetics in the therapeutic dose range and its steady-state pharmacokinetics are predictable from single dose data. Steady-state is reached with the second dose when the drug is given once daily and the peak-trough fluctuations in plasma concentration is minimal. Plasma-concentrations of nisoldipine increase with age. Careful dose titration according to individual clinical response is recommended in the elderly. Nisoldipine CC should not be used in patients with liver cirrhosis, though dosage adjustments in patients with renal impairment are not necessary. Inter-ethnic differences in its pharmacokinetics are not evident. Owing to inhibition of metabolising enzymes, a small dosage adjustment decrement for nisoldipine CC may be required when it is given in combination with cimetidine. Concomitant ingestion of nisoldipine with grapefruit juice should be avoided. Inducers of cytochrome P450 (CYP) 3A4, e.g. rifampicin (rifampin) and phenytoin should not be combined with nisoldipine CC, as they may reduce its bioavailability and result in a loss of efficacy. The concomitant use of other drugs which may produce marked induction or inhibition of CYP3A4 is contraindicated. Concomitant intake of the CC tablet with high fat, high calorie foods resulted in an increase in the maximum plasma concentrations of nisoldipine. The 'food-effect' can be avoided by administration of the CC tablet up to 30 minutes before the intake of food [corrected]. Plasma concentrations of nisoldipine are related to its antihypertensive effect via a maximum effect model. Nisoldipine CC once daily produce reductions in blood pressure which are maintained over 24 hours in the absence of relevant effects on heart rate.

The development of matrix tablets for diclofenac sodium based on an empirical in vitro and in vivo correlation

Different dissolution media were tested using Voltaren SR ® as a model dosage form to develop an in vitro/in vivo correlation for diclofenac sodium. An empirical correlation between the cumulated amount of in vitro dissolution (%) and cumulated AUC (%) was constructed by selecting an appropriate time scale. Dissolution in a water medium for 1 h, followed with simulated intestinal fluid seemed to give better correlation with the AUC in vivo. This approach was tested with four matrix tablets based on hydroxypropylmethylcellulose (HPMC) of varying grades of viscosity and at different ratios. The closeness between in vitro dissolution profile and cumulated AUC change was conclusively demonstrated for these four matrix tablets. Based on this result, a product named Clofen SR ® was then designed and was tested in vivo to compare its relative bioavailability with that of Voltaren SR ®. The results demonstrated a similar extent of absorption in terms of AUC for Clofen SR ® as for Voltaren SR ®. However, the fluctuation in plasma concentration was smaller for Clofen SR ® than for Voltaren SR ® at steady state based on the three pharmacokinetic parameters of C max(ss), C min(ss), and Fluctuation (ss). It is concluded that this empirical correlation may be able to predict the relative extent of absorption, but fails to indicate the possible erratic concentration change of diclofenac sodium in the plasma.

Nisoldipine CC: efficacy and tolerability in hypertension and ischemic heart disease.

Nisoldipine is a second-generation dihydropyridine calcium channel blocker (CCB). It is the most vascular selective of the currently available CCBs, and thus has the capacity to lower blood pressure without affecting the functioning of the myocardium and skeletal muscle, and without producing any negative inotropic effects. Nisoldipine coat core (CC) is an extended-release formulation that allows nisoldipine to be released gradually over 24 hours, minimizing fluctuations in plasma concentration and providing a good trough/peak ratio. It has a slow onset and long duration of action, and ambulatory blood pressure monitoring has demonstrated that its antihypertensive effect is maintained over 24 hours with no evidence of reflex tachycardia, hypotension, or sympathetic neurohormonal activation and no effects on circadian variation. Studies in patients with hypertension have shown that nisoldipine CC provides reductions in blood pressure that are at least equivalent to those seen with diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, and other CCBs, without deleterious effects on metabolic parameters. In particular, it has been found to be effective in elderly patients and in black patients with severe hypertension. The DEFIANT studies have demonstrated that nisoldipine CC improves cardiac function and exercise tolerance in patients recovering from acute myocardial infarction, without increasing the risk of mortality compared with placebo. It also improves exercise performance in patients with stable angina pectoris. Nisoldipine CC is well tolerated in all groups of patients, with the most frequently reported side effects being headache and peripheral edema, which are usually mild and transient.