Lower Maximum Plasma Concentration Research Articles

Pharmacokinetic and pharmacodynamic comparison of epinephrine, administered intranasally and intramuscularly: An integrated analysis

BackgroundManual intramuscular epinephrine injection is the standard of care for treating severe allergic reactions and anaphylaxis. Epinephrine autoinjectors were approved on the basis of the assumption that their pharmacokinetic and pharmacodynamic profiles are equivalent to manual intramuscular injection; however, although there is emerging evidence for product-related differences in pharmacokinetic profiles, very little is known about the comparative pharmacodynamic profiles. ObjectiveTo compare pharmacokinetic and pharmacodynamic profiles of epinephrine delivered through manual intramuscular injection, autoinjectors, and intranasal spray. MethodsThis integrated analysis was based on data from 4 randomized cross-over phase 1 trials that compared the pharmacokinetics and pharmacodynamics of epinephrine using manual intramuscular epinephrine 0.3 mg injection, epinephrine 0.3 mg autoinjectors (Symjepi and EpiPen), and epinephrine 1 mg intranasal spray (neffy). ResultsData from 175 participants showed that although neffy (1.0 mg intranasal spray) resulted in a maximum concentration (258 pg/mL) that was lower than or comparable with manual epinephrine intramuscular injection (254 pg/mL), Symjepi (438 pg/mL) and EpiPen (503 pg/mL), it led to comparable increases in systolic blood pressure (maximum effect [Emax], 16.9, 10.9, 14.9, and 18.1 mm Hg, respectively). The effect of neffy on diastolic blood pressure was also markedly more pronounced than that of other products (Emax, 9.32, 5.51, 5.78, and 5.93 mm Hg, respectively). ConclusionIntranasal delivery of epinephrine using neffy increases systolic blood pressure more efficiently than do manual intramuscular injection and epinephrine autoinjectors, despite lower maximum plasma concentrations.

A Population Pharmacokinetic Analysis of PF-5190457, a Novel Ghrelin Receptor Inverse Agonist in Healthy Volunteers and in Heavy Alcohol Drinkers.

The ghrelin receptor (GHS-R1a) is a potential target for alcohol use disorders. PF-5190457 is the first inverse agonist of GHS-R1a to progress to clinical development with potential to treat alcohol use disorder. We present a population pharmacokinetic model for PF-5190457 in non-heavy (alcohol consumption status = 0) and heavy alcohol drinkers (alcohol consumption status = 1), and identify relevant factors that can influence its pharmacokinetics. Plasma concentration-time data from non-heavy (n = 35) and heavy drinkers (n = 12) were pooled for the population pharmacokinetic model development. The influence of various covariates including alcohol consumption status was evaluated. The accuracy, precision, and robustness of the model were also evaluated using bootstrapping and visual predictive checks. A two-compartment model best described the pharmacokinetics of PF-5190457. The apparent volume of distribution of 44.5 L, apparent clearance of 72.0 L/h, apparent peripheral volume of distribution of 271 L, apparent distributional clearance of 28.7 L/h, and first-order absorption rate constant of 0.27/h were accurate and precise. The apparent volume of distribution was 3.8-fold higher (169 L) in heavy drinkers, and correlated with a lower maximum plasma concentration in heavy drinkers compared with non-heavy drinkers at the same dose; and a corresponding reduced incidence of somnolence in heavy drinkers at doses > 50mg. This work provides an accurate, precise, and robust two-compartment model that describes the pharmacokinetics of PF-5190457 and suggests a possible link of PF-5190457 pharmacokinetics with somnolence. ClinicalTrials.gov identifier numbers NCT01247896 and NCT02039349.

Catechin Bioavailability Is Reduced in Obese Persons Without Altering Gut Microbial-Derived Valerolactones Following Consumption of a Green Tea Extract Confection

Abstract Objectives Green tea extract (GTE) protects against obesity in rodents by reducing gut permeability that otherwise provokes endotoxemia-mediated inflammation. However, whether obesity affects catechin bioavailability and microbial metabolism is unknown. We hypothesized that obesity will reduce catechin bioavailability by increasing microbial biotransformation of catechins. Methods Obese persons (n = 10 M/7F; 33.5 ± 0.7 kg/m2) and age-matched healthy persons (n = 10 M/9F; 21.7 ± 0.4 kg/m2) completed a pharmacokinetics (PK) trial in which a GTE confection [290 mg epigallocatechin gallate (EGCG), 87 mg epigallocatechin (EGC), 39 mg epicatechin (EC), 28 mg epicatechin gallate (ECG)] was ingested prior to collecting plasma at 0, 0.25, 0.5, 1, 2, 3, 5, 8, 10, and 12 h and urine from 0–4, 4–8, 8–12, and 12–24 h. Stool samples were collected and gut permeability was assessed prior to the 12-h PK trial. Plasma and urinary catechin/catechin-derived microbial metabolites were assessed following enzymatic hydrolysis by LC-MS. Results Regardless of health status, relative bioavailability, based on plasma area under the curve (AUC0–12 h), of GTE catechins were: EGCG > EGC > ECG > EC. However, obese persons had 24–27% lower plasma AUC0–12 h for the four catechins compared to lean persons (P < 0.05). They also had 18–36% lower maximum plasma concentrations (Cmax) of GTE catechins but 12 h plasma catechin concentrations were unaffected by obesity status (P > 0.05). 3ʹ,4ʹ-γ-valerolactone (3,4-VL) was detected in the plasma of all participants, while 3ʹ,4ʹ,5ʹ-γ-valerolactone (3,4,5-VL) was detected in 74% and 82% of lean and obese persons, respectively. Plasma AUC0–12 h for these VL metabolites did not differ by obesity status. EGC, EC, 3,4-VL, and 3,4,5-VL, but not EGCG and ECG, were primarily present in urine and urinary total VLs were increased compared with total urinary catechins. However, 24-h urinary excretion of catechins and VLs were unaffected by obesity. Conclusions Obesity reduces GTE catechin bioavailability and Cmax independent of any change in VL metabolite appearance or urinary elimination of catechins, suggesting a gut-level mechanism that limits catechin absorption. Funding Sources Supported by USDA-NIFA and the Foods for Health Discovery Theme at The Ohio State University.

Effect of ABCB1 Genotypes on the Pharmacokinetics and Clinical Outcomes of New Oral Anticoagulants: A Systematic Review and Meta-analysis.

New Oral Anticoagulants (NOACs) are effective and widely used to prevent and treat thromboembolic diseases, but the response to NOACs differs according to ABCB1 genotypes. We investigated the effects of ABCB1 genotypes on the pharmacokinetics and clinical outcomes of NOACs. We searched PubMed, Embase, and the Cochrane Library for studies on ABCB1 genotypes published from the inception of these databases until May 23, 2018. The Weighted Mean Difference (WMD) and Odds Ratio (OR) with 95% Confidence Interval (CI) were calculated for continuous and dichotomous data, respectively. Summary results were calculated using a random effects model. Ten studies involving 2609 individuals were included in the systematic review, and three studies involving 535 individuals were included in the meta-analysis. Overall, four ABCB1 single-nucleotide polymorphisms were identified in the review. Carriers of the ABCB1 rs1045642 CC genotype had lower maximum plasma concentration (Cmax) than those of TT (WMD = -16.99 ng/mL; 95% CI = -33.39 to -0.59; P = 0.04), and carriers of the rs2032582 GG genotype showed lower Cmax than those of the A/T allele (WMD = -19.21 ng/mL; 95% CI = -36.62 to -1.80; P = 0.03). Carriers of the rs1045642 CC genotype showed lower area under the curve from time 0 to infinity (AUC0-∞) than those of the T allele (WMD = -78.58 ng·h/mL; 95% CI = -151.14 to -6.01; P = 0.03). ABCB1 rs4148738 genotypes did not affect the risks of ischemic stroke or systemic embolism (OR = 0.88), ischemic events (OR = 0.98), bleeding (OR = 0.94), major bleeding (OR = 1.14), or minor bleeding (OR = 0.94) in patients treated with dabigatran. Cmax was lower in carriers of ABCB1 rs1045642 CC than in those of TT and in carriers of rs2032582 GG than in those of the A/T allele, and AUC0-∞ was lower in carriers of rs1045642 CC than in those of TT. Conversely, ABCB1 rs4148738 genotypes did not affect primary clinical endpoints in dabigatran-administered patients. Future studies should analyze the relationships of ABCB1 genotypes with the pharmacokinetics and clinical outcomes of specific NOACs.

Antiobesity and emetic effects of a short-length peptide YY analog and its PEGylated and alkylated derivatives

Neuropeptide Y2 receptor (Y2R) agonism is an important anorectic signal and a target of antiobesity drug discovery. Recently, we synthesized a short-length Y2R agonist, PYY-1119 (4-imidazolecarbonyl-[d-Hyp24,Iva25,Pya(4)26,Cha27,36,γMeLeu28,Lys30,Aib31]PYY(23–36), 1) as an antiobesity drug candidate. Compound 1 induced marked body weight loss in diet-induced obese (DIO) mice; however, 1 also induced severe vomiting in dogs at a lower dose than the minimum effective dose administered to DIO mice. The rapid absorption of 1 after subcutaneous administration caused the severe vomiting. Polyethylene glycol (PEG)- and alkyl-modified derivatives of 1 were synthesized to develop Y2R agonists with improved pharmacokinetic profiles, i.e., lower maximum plasma concentration (Cmax) and longer time at maximum concentration (Tmax). Compounds 5 and 10, modified with 20 kDa PEG at the N-terminus and eicosanedioic acid at the Lys30 side chain of 1, respectively, showed high Y2R binding affinity and induced significant body weight reduction upon once-daily administration to DIO mice. Compounds 5 and 10, with their relatively low Cmax and long Tmax, partially attenuated emesis in dogs compared with 1. These results indicate that optimization of pharmacokinetic properties of Y2R agonists is an effective strategy to alleviate emesis induced by Y2R agonism.

Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine Exposure and Duration of Efficacy.

Lisdexamfetamine dimesylate (LDX) is a long-acting d-amphetamine prodrug used to treat attention-deficit/hyperactivity disorder (ADHD) in children, adolescents and adults. LDX is hydrolysed in the blood to yield d-amphetamine, and the pharmacokinetic profile of d-amphetamine following oral administration of LDX has a lower maximum plasma concentration (Cmax), extended time to Cmax (Tmax) and lower inter- and intra-individual variability in exposure compared with the pharmacokinetic profile of an equivalent dose of immediate-release (IR) d-amphetamine. The therapeutic action of LDX extends to at least 13 h post-dose in children and 14 h post-dose in adults, longer than that reported for any other long-acting formulation. Drug-liking scores for LDX are lower than for an equivalent dose of IR d-amphetamine, which may result from the reduced euphorigenic potential associated with its pharmacokinetic profile. These pharmacokinetic and pharmacodynamic characteristics of LDX may be beneficial in the management of symptoms in children, adolescents and adults with ADHD.

Pharmacokinetic effect of combined administration on spinosin and ferulic acid in monarch drug Ziziphi Spinosae Semen kernel

To study the pharmacokinetic effect of different combined administration with monarch drug Ziziphi Spinosae Semen on its main components in rats. Sprague-Dawley (SD) rats were randomly divided into Ziziphi Spinosae Semen group, Ziziphi Spinosae Semen-Fructus Schisandrae Chinensis group, Ziziphi spinosae Semen-Salviae Miltiorrhize Radix et Rhizoma group and Zaoren Ansheng prescription group. After oral administration, HPLC was eluted with the mobile phase of acetonitrle-0.03% phosphate acid water in a gradient mode. The detection wavelength was 280 nm. The pharmacokinetic parameters of spinosin and ferulic acid were calculated by DAS 2. 0 software. Compared with Ziziphi Spinosae Semen group, Ziziphi Spinosae Semen-Fructus Schisandrae Chinensis group, Ziziphi Spinosae Semen-Salviae miltiorrhizae Radix et Rhizoma group showed a lower maximum plasma concentration (C(max)) and area under curve (AUC(0-t)) for spinosin and ferulic acid but higher clearance speed (CL/F); whereas the Zaoren Ansheng prescription group showed higher maximum plasma concentration (C(max)) and area under curve (AUC(0-t)) for spinosin and ferulic acid but lower clearance speed (CL/F). Compared with Ziziphi Spinosae Semen group, prescription group showed slower metabolism of spinosin and ferulic

Pharmacokinetic alteration of baclofen by multiple oral administration of herbal medicines in rats.

The potential pharmacokinetic (PK) interaction of conventional western drug, baclofen, and oriental medications Oyaksungisan (OY) and Achyranthes bidentata radix (AB) extract for the treatment of spasticity has been evaluated. Rats were pretreated with distilled water (DW), OY, or AB extract by oral administration every day for 7 days. After 10 min of the final dose of DW or each herbal medication, baclofen (1 mg/kg) was given by oral administration and plasma concentrations of baclofen were determined by LC/MS/MS. The plasma baclofen concentration-time profiles were then analyzed by noncompartmental analysis and a population PK model was developed. Baclofen was rapidly absorbed, showed biexponential decline with elimination half-life of 3.42–4.10 hr, and mostly excreted into urine. The PK of baclofen was not affected by AB extract pretreatment. However, significantly lower maximum plasma concentration (C max) and longer time to reach C max (T max) were observed in OY pretreated rats without changes in the area under the curve (AUC) and the fraction excreted into urine (F urine). The absorption rate (K a) of baclofen was significantly decreased in OY pretreated rats. These data suggested that repeated doses of OY might delay the absorption of baclofen without changes in extent of absorption, which needs further evaluation for clinical significance.

Pharmacodynamics and Pharmacokinetics of a Novel, Low-Dose, Soft-Gel Capsule of Acetylsalicylic Acid in Comparison with an Oral Solution After Single-Dose Administration to Healthy Volunteers: A Phase I, Two-Way Crossover Study

Low-dose acetylsalicylic acid (ASA; aspirin) is well-established as a platelet anti-aggregating agent for the secondary prevention of cardiovascular events. The objective of this study was to investigate the non-inferiority of a novel ASA 75 mg soft-gel capsule formulation compared with a marketed powder for oral solution in terms of reduction in serum thromboxane B2 (TXB2), a surrogate for platelet aggregation. Pharmacokinetics and tolerability of the products were also investigated. In this randomised, two-way crossover study, 46 male and female healthy subjects received a single dose of the investigational products in two periods separated by a 14-day washout. Serum TXB2 and plasma ASA were determined up to 24 h post-dose. Maximum percentage of TXB2 inhibition (I max) and area under the inhibition-time curve (AUICt) were calculated. Non-inferiority was assumed if the lower limits of the 95 % confidence intervals (CIs) for the two pharmacodynamic parameters were above 85 %. The 95 % CI lower limits were 95.35 % for I max and 86.12 % for AUICt, i.e. within the pre-specified delta. Time to achieve I max did not differ between treatments (p = 0.88). The two formulations were bioequivalent as regards the extent of ASA exposure (area under the plasma concentration-time curve from zero to time t [AUCt] 90 % CIs 96.67-113.37); a delayed ASA absorption (later time to reach maximum plasma concentration [t max], lower maximum plasma concentration [C max]) was observed for the test product. No treatment-related adverse events were reported. In healthy subjects, the 75 mg soft-gel capsules were not inferior to the oral solution in terms of serum TXB2 inhibition, indicating that the novel formulation could be an effective alternative in the secondary prevention of cardiovascular events.

Switch from intravenous to enteral moxifloxacin in critically ill patients: A pilot study

Critically ill patients generally receive moxifloxacin intravenously to achieve rapid bacterial killing. An early switch from intravenous to enteral moxifloxacin may be considered because of its good oral bioavailability in healthy volunteers. Since bioavailability may be altered in critically ill patients due to pathophysiological changes, this study aimed to investigate whether enteral moxifloxacin is bioequivalent to intravenous moxifloxacin in such patients. Blood samples were obtained from 4 critically ill patients before and at serial time-points after intravenous and enteral administration. In all patients, lower maximum plasma concentration (C(max)) and area under the plasma concentration-time curve during the 24-h observation period (AUC(24h)) values were observed after enteral administration compared to those after intravenous administration. This resulted in lower C(max)/minimum inhibitory concentration (MIC) and AUC(24h)/MIC values, which are 2 indices predicting the antibacterial efficacy of moxifloxacin. Despite the limited number of subjects, we conclude that a switch from intravenous to enteral moxifloxacin is not recommended in these patients, because the 2 administration forms are not bioequivalent.

Twelve‐Month Tolerability and Efficacy Study of NP101, the Sumatriptan Iontophoretic Transdermal System

To assess the long-term tolerability and efficacy of NP101, a novel transdermal sumatriptan patch being developed for the acute treatment of migraine. Nausea (with or without vomiting) and gastroparesis have been characterized as being among the most problematic challenges affecting migraine care today. Migraine-associated nausea can cause patients to delay or avoid taking oral medication with a resultant loss or reduction of therapeutic efficacy. Migraine-associated gastroparesis can impair absorption and reduce bioavailability of oral migraine medications and thereby reduce and delay therapeutic efficacy. The non-oral triptan formulations that have been used to overcome these challenges are associated with other shortcomings that can limit their use. Designed to overcome these shortcomings and treatment limitations imposed by gastrointestinal signs and symptoms, the NP101 patch avoids the need for oral administration, does not depend upon gastrointestinal absorption, and provides more consistent, predictable plasma concentrations than oral and intranasal formulations of sumatriptan and a lower maximum plasma concentration than sumatriptan injection. Patients diagnosed with migraine who had participated in a randomized, double-blind, Phase III study of the NP101 patch were given the option to use NP101 to treat migraine episodes with moderate or severe headache pain for up to 12 months in this open-label trial. One hundred eighty-three patients applied 2089 study patches. The most common adverse events involved the patch application site (45% of patients). The only non-application-site adverse events reported in >2% of patients were nausea (n=6, 3.3%), upper respiratory tract infection (n=6, 3.3%), and nasopharyngitis (n=4, 2.2%). The incidence of triptan-associated adverse events was 1.6%. Across all visits for investigator assessments, the majority of patients (ranging from 74.7% at Month 1 to 92.2% at Month 9) were scored as having no erythema at patch application sites. For patient assessments, the percentage of patch placement sites scored as having no or minimal redness was 38.2% at the time of patch removal and 65.4% 24 hours after patch activation. Two hours after patch activation across all patch treatments over the 12-month study, 23.8% of initial acute migraine episodes were scored as being free from headache pain, 58.2% as having headache pain relief,78.9% as nausea free, 60.1% as phonophobia free, 53.4% as photophobia free, and 20.7% as migraine free. No evidence of waning tolerability or efficacy was observed over the 12-month study period. NP101, a transdermal sumatriptan formulation in development for the acute treatment of migraine, demonstrated tolerability and efficacy with successive uses over 12 months in this clinical trial.

A pharmacokinetic and bioequivalence study of Contiflo ICON 400 µg tablets in healthy Indian subjects

Tamsulosin, an alpha1 adrenoceptor blocking agent, exhibits selectivity for alpha1 receptors in human prostate. Blockade of these adrenoceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of benign prostatic hypertrophy. A new formulation Contiflo ICON 400 µg has been developed by Ranbaxy Laboratories Limited, India similar to Flomaxtra XL 400 µg of Astellas Pharma Limited, United Kingdom. This product is specifically designed to achieve a more consistent plasma concentration over a period of 24-h, a lower maximum plasma concentration (Cmax) and an independence of pharmacokinetics (PKs) on food intake. The objective of the present study was to evaluate the pharmacokinetics and bioequivalence of the new formulation Contiflo ICON 400 µg of Ranbaxy Laboratories Limited, India and Flomaxtra XL 400 µg prolonged release tablets (containing tamsulosin hydrochloride prolonged release 400 µg) of Astellas Pharma Limited, United Kingdom. Study was conducted as an open label, balanced, randomized, two-treatment, two-period, two-sequence, cross over, single-dose bioequivalence study in 32 adult male human subjects under fed conditions. The mean (range) age, weight and height of the study subjects were 27.03 years (19 - 40 years), 57.19 kg (48 - 72 kg) and 166.81 cm (154 - 181 cm) respectively. Blood samples were collected at pre-dose and at 0.5, 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 9, 10, 12, 16, 20, 24, 36, 48, 72, and 96 h post dose in each period. Plasma samples were analyzed for tamsulosin by using validated liquid chromatographic mass spectrometry (LC-MS/MS) method. The Mean ± SD of pharmacokinetic parameters tmax, Cmax, AUC24, AUClast and AUCinf for Tamsulosin were 11.741 ± 4.7201 and 12.155 ± 6.3077 h, 10.7614 ± 4.76709 and 10.4954 ± 5.08979 ng/ml, 171.4674 ± 77.39695 and 160.6738 ± 77.98628 ng.h/ml, 262.7771 ± 150.21432 and 250.6854 ± 156.75581 ng.h/ml, 280.0702 ± 152.14253 and 273.5078 ± 156.85910 ng.h/ml for test and reference formulations respectively. The ratios of least square means and the 90% confidence interval of log transformed pharmacokinetic parameter Cmax, AUC24, AUClast and AUCinf were within 80 - 125% acceptance range. In conclusion, Contiflo ICON 400 µg tablets developed by Ranbaxy Laboratories Limited is bioequivalent to the reference formulation in healthy adult male volunteers under fed condition.

Pharmacokinetics of oligonucleotides.

The effectiveness of antisense oligonucleotides as therapeutic agents depends on their pharmacokinetics, tissue disposition, stability, elimination and safety profile. Pharmacokinetic data allow one to determine the frequency of administration and any potential toxicity associated with chronic administration. Phosphorothioate oligonucleotides degrade from the 3' end, the 5' end, and both the 3' and 5' ends in a time- and tissue-dependent manner. After intravenous administration in mice, rats and monkeys, phosphorothioate oligonucleotides are detected in plasma; they distribute rapidly and are retained in the majority of tissues. The major route of elimination is the urine. The pharmacokinetic profile is similar following subcutaneous, intradermal or intraperitoneal administration, but with lower maximum plasma concentrations. Phosphorothioate oligonucleotides have a short plasma half-life in humans. End-modified, mixed-backbone oligonucleotides (MBOs) contain nuclease-resistant 2'-O-alkylribonucleotides or methylphosphonate internucleotide linkages at both the 3' and 5' ends of phosphorothioate oligonucleotides. These end-modified MBOs have pharmacokinetic profiles similar to those of the parent phosphorothioate oligonucleotides, but they are significantly more stable in vivo and they can be administered orally. Centrally modified MBOs contain modified RNA or DNA in the centre of a phosphorothioate oligonucleotide. They show controlled degradation and elimination following administration in rats. The pharmacokinetics of antisense oligonucleotides depends on the sequence, the nature of the oligonucleotide linkages and the secondary structure.

Pharmacokinetic profile of tamsulosin OCAS

The tamsulosin oral‐controlled absorption system (OCAS®) is a new tablet formulation of the α1‐adrenoceptor (α1‐AR) antagonist tamsulosin, which is used for treating lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH). The tablet uses the OCAS technology, which was specifically designed to give a more continuous 24‐h release of tamsulosin, resulting in a more consistent and continuous 24‐h plasma concentration, a lower maximum plasma concentration (Cmax) and an independence of pharmacokinetics (PKs) on food intake. It was expected that the improved PK profile would translate into a better control of day‐ and night‐time symptoms of BPH and a lower risk of adverse events. Phase I PK studies showed that tamsulosin OCAS indeed has a flattened PK profile with a lower Cmax and a more stable and consistent 24‐h concentration of tamsulosin, independent of food intake, compared to conventional tamsulosin. A study combining γ‐scintigraphy and PK analysis of blood samples confirmed that the improved PK profile of tamsulosin OCAS is attributed to the tablet being consistently and continuously released throughout the entire gastrointestinal tract, including the colon.

The Pharmacokinetic Profile of Tamsulosin Oral Controlled Absorption System (OCAS ®)

Context: A new formulation of tamsulosin for the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) has been developed. This formulation uses the proprietary oral controlled absorption system (OCAS ®) technology which has the potential to better control the release during passage of the gastrointestinal tract including the colon and which may be devoid of a food effect. This study describes the characteristics of the tamsulosin OCAS formulation with respect to single and multiple dose human pharmacokinetics (PK). Methods: The single dose PK of three tamsulosin OCAS 0.4 mg formulations (S2, S3 and S4) in comparison with tamsulosin modified release (MR) 0.4 mg capsules were analysed in 12 young healthy volunteers in a 4-way crossover study to allow selection of a candidate for further development. 24 young healthy volunteers were subsequently recruited to compare multiple dose PK for tamsulosin OCAS 0.4, 0.8 and 1.2 mg S3 formulation under fasted conditions with tamsulosin OCAS 0.4 mg under fed conditions in a 4-way crossover study. Results: The tamsulosin OCAS S3 formulation was selected for further development. This chosen formulation shows distinctively different PK from the commercially available tamsulosin MR capsules with a lower maximum plasma concentration ( C max), a slightly lower area under the curve (AUC) and reduced fluctuation in 24-hour plasma concentrations/improved C max/ C 24h ratio while showing dose linearity and an unchanged elimination half-life. It will allow once daily dosing in the treatment of LUTS/BPH. In addition, tamsulosin OCAS does not have a food effect unlike the MR capsules. Conclusions: Tamsulosin OCAS shows improved PK compared with the standard MR capsules. Such improved PK may translate in an improvement of the efficacy/safety ratio during the treatment of LUTS/BPH. Demonstration of such potential benefits as well as the establishment of the daily dose will require subsequent confirmatory clinical studies.

Lovastatin extended release: a review of its use in the management of hypercholesterolaemia.

Lovastatin extended release (ER) provides a new form of delivery for lovastatin, an HMG-CoA reductase inhibitor. Lovastatin ER delivers the drug in a more sustained fashion, as shown by a smoother plasma concentration-time profile, a lower maximum plasma concentration and a prolonged half-life compared with that of lovastatin immediate release (IR). At dosages of 10-60 mg/day, lovastatin ER significantly reduced levels of total cholesterol, low density lipoprotein (LDL)-cholesterol and triglycerides, and increased levels of high density lipoprotein-cholesterol, in patients with primary hypercholesterolaemia in a randomised, double-blind study of 12 weeks' duration. These effects were maintained in a 6-month extension study in which patients received lovastatin 40 or 60 mg/day. In a randomised 4-week study in 24 patients with primary hypercholesterolaemia, the reduction in plasma LDL-cholesterol levels was significantly greater with lovastatin ER 40 mg/day than with the IR formulation administered at the same dosage. Lovastatin ER was well tolerated in all studies and adverse events were usually mild to moderate and transient. The tolerability profile of lovastatin ER was similar to that of lovastatin IR. There were no reports of clinically relevant elevations in liver transaminases or creatine phosphokinase attributed to the drug in recipients of lovastatin ER. The ER formulation of lovastatin provides smooth and sustained delivery of this established and well-tolerated agent over the dosage interval, significantly reducing LDL-cholesterol in patients with primary hypercholesterolaemia. If, as expected, the beneficial changes in lipid levels are maintained during long-term treatment and further clinical experience confirms the greater efficacy of the lovastatin ER formulation than the IR formulation, then lovastatin ER is likely to supplant lovastatin IR and provide a useful option in the management of patients with dyslipidaemia and prevention of coronary heart disease.

Spotlight on Lovastatin Extended Release in Hypercholesterolemia1

Lovastatin extended release (ER) provides a new form of delivery for lovastatin, an HMG-CoA reductase inhibitor. Lovastatin ER delivers the drug in a more sustained fashion, as shown by a smoother plasma concentration-time profile, a lower maximum plasma concentration, and a prolonged half-life compared with that of lovastatin immediate release (IR). At dosages of 10–60 mg/day, lovastatin ER significantly reduced levels of total cholesterol, low density lipoprotein (LDL)-cholesterol and triglycerides, and increased levels of high density lipoprotein-cholesterol, in patients with primary hypercholesterolemia in a randomized, double-blind study of 12 weeks’ duration. These effects were maintained in a 6-month extension study in which patients received lovastatin 40 or 60 mg/day. In a randomized 4-week study in 24 patients with primary hypercholesterolemia, the reduction in plasma LDL-cholesterol levels was significantly greater with lovastatin ER 40 mg/day than with the IR formulation administered at the same dosage. Lovastatin ER was well tolerated in all studies and adverse events were usually mild to moderate and transient. The tolerability profile of lovastatin ER was similar to that of lovastatin IR. There were no reports of clinically relevant elevations in liver transaminases or creatine phosphokinase attributed to the drug in recipients of lovastatin ER. The ER formulation of lovastatin provides smooth and sustained delivery of this established and well tolerated agent over the dosage interval, significantly reducing LDL-cholesterol in patients with primary hypercholesterolemia. If, as expected, the beneficial changes in lipid levels are maintained during long-term treatment and further clinical experience confirms the greater efficacy of the lovastatin ER formulation than the IR formulation, then lovastatin ER is likely to supplant lovastatin IR and provide a useful option in the management of patients with dyslipidemia and prevention of coronary heart disease

The Clinical Pharmacokinetics of Rifabutin

Rifabutin is structurally similar to rifampin, but there are important pharmacokinetic differences between the two drugs. Rifabutin is more lipid soluble than is rifampin, resulting in more-extensive tissue uptake, a larger volume of distribution, lower maximum plasma concentrations, lower trough concentrations, a longer terminal half-life, and higher tissue-to-plasma drug concentration ratios. The oral bioavailability of rifabutin is low. Like rifampin, rifabutin induces its own metabolism during multiple dosing. Rifabutin is extensively metabolized. The two major metabolites of rifabutin contribute to its antimicrobial activity. Rifabutin induces hepatic metabolism but is not as potent an inducer as is rifampin. Rifabutin does not affect the pharmacokinetics of antiretroviral drugs that are excreted in the urine. Although rifabutin decreases plasma concentrations of zidovudine, this finding does not appear to be clinically relevant. When administered during rifabutin prophylaxis, fluconazole decreases the incidence of Mycobacterium avium complex bacteremia. The coadministration of clarithromycin and rifabutin results in increased plasma concentrations of rifabutin and decreased plasma concentrations of clarithromycin; however, the plasma concentration of clarithromycin's active metabolite is increased.