Population pharmacokinetic modeling of pantoprazole in pediatric patients from birth to 16 years.

The population pharmacokinetics of pantoprazole was characterized in pediatric patients from birth to 16 years using NONMEM and evaluated via bootstrap and predictive check. Data were described using a 2-compartment model with a typical parameterized in terms of clearance (CL) (95% CI) of 1.93 L per hour (1.53, 2.61), given the reference covariates (female, full term, extensive/unknown CYP2C19 metabolizer status, non-African American, 10 kg weight, intravenous or tablet administration). Pantoprazole pharmacokinetic parameters appear to be similar in pediatric patients compared to adults when allometrically scaled. The effect of age on allometrically scaled CL was best described by a sigmoid Emax model with the age effect reaching an asymptote approximately equal to the adult CL by 1 year. CYP2C19 poor metabolizers exhibited reduced CL with the point estimate and 95% CI more than 70% lower than the typical value. Simulations from the final model indicated that the 1.2-mg/kg dose provides the best comparison to adults.

Clinical evaluation of moroctocog alfa (AF-CC), a new generation of B-domain deleted recombinant factor VIII (BDDrFVIII) for treatment of haemophilia A: demonstration of safety, efficacy, and pharmacokinetic equivalence to full-length recombinant factor VIII.

BDDrFVIII is a B-domain deleted recombinant factor VIII (rFVIII) product for haemophilia A. Manufacture uniquely includes purification chromatography by synthetic-affinity ligand rather than murine-based monoclonal antibody, as well as an albumin-free cell culture process. BDDrFVIII was studied in 204 patients, including 62 subjects <16 years old, in two studies. A double-blind, randomized, pharmacokinetic (PK) crossover study, utilizing a central laboratory assay (one-stage (OS)) for both drug potency assignment and plasma FVIII-activity measurements, demonstrated that BDDrFVIII was PK-equivalent to a full-length rFVIII. Favourable efficacy and safety were observed: during defined routine prophylaxis in a patient population significant for preexisting target joints, nearly half (45.7%) of patients had no bleeding, and a low-annualized bleed rate (ABR) was achieved (median 1.9); 92.5% of haemorrhages (n = 187) required < or =2 infusions. Three subjects (1.5%, across both studies) developed de novo inhibitors (low-titre, transient), and the primary safety endpoint, based on a prospective Bayesian analysis, demonstrated the absence of neoantigenicity for BDDrFVIII. The PK-equivalence, based on central testing to align test and reference articles, and the novel Bayesian analysis of inhibitor safety in these investigations reflect robust experimental designs with relevance to future studies. This extensive dataset demonstrates the safety and efficacy of BDDrFVIII for haemophilia A.

Reformulated BeneFix: efficacy and safety in previously treated patients with moderately severe to severe haemophilia B.

BeneFix, the only recombinant factor IX (FIX), has been reformulated. The reformulation involves a change in diluent and allows for more concentrated infusions of recombinant FIX. A double-blind, randomized, pharmacokinetic (PK) crossover study demonstrated that reformulated BeneFix was bioequivalent to original BeneFix and follow-up PK evaluation after 6 months of treatment demonstrated the PK stability of reformulated BeneFix after multiple exposures. Favourable efficacy and safety profiles, consistent with those already well-established for original BeneFix, were observed: 81.1% of haemorrhages resolved with only a single infusion; 85.3% of initial treatment response ratings were Excellent or Good; more than half of the subjects using reformulated BeneFix for routine prophylaxis (11 of 17, 64.7%) had no spontaneous haemorrhages during their 6-12 month course of prophylactic treatment, with an overall spontaneous bleeding rate of 0.72 year(-1); and for the single surgical procedure (knee washing), treatment was rated Useful. In addition, there was no FIX inhibitor development, allergic-type manifestations, or thrombogenic complications with more than 1100 infusions (nearly 5.2 million IUs) administered in this trial. All efficacy and safety outcomes from this study were achieved with more concentrated recombinant protein infusions than that possible with original BeneFix, and utilization of the 2000 IU per vial dosage strength, newly introduced with the reformulated product, was high (>62%). The reformulation of BeneFix allows smaller delivery volumes and an increased choice of dosage strengths without altering the PK properties (including incremental recovery and half-life) or the established efficacy and safety profile of recombinant FIX.

ReFacto and Advate: a single-dose, randomized, two-period crossover pharmacokinetics study in subjects with haemophilia A.

ReFacto is a recombinant B-domain-deleted, monoclonal antibody-purified, solvent-detergent-treated factor VIII (BDDrFVIII) with no albumin added to the final formulation. Although ReFacto has been shown to be bioequivalent to a plasma-derived FVIII product (Hemophil-M) in a randomized, crossover pharmacokinetic (PK) study, the comparability of ReFacto with the full-length (complete sequence) recombinant FVIII (FLrFVIII, Advate) product has not been previously examined in this manner. The primary objective of this study was to compare the PKs of ReFacto with those of Advate in patients with severe haemophilia A. This was a third-party unblinded, randomized, multicentre, two-period crossover PKs study of ReFacto and Advate in subjects with severe haemophilia A (FVIII:C < or =1%). Blood samples were collected over a 48-h period after i.v. administration of each of the FVIII products. FVIII:C was determined using the chromogenic substrate assay (CSA) in a central laboratory. The plasma FVIII:C PK parameters of ReFacto and Advate were determined using non-compartmental analysis. Bioequivalence was assessed on maximum plasma concentration (C(max)) and the area under the plasma concentration vs. time curves (AUCs) using an anova. The two products were judged to be equivalent if the 90% confidence limits of the ratio of the geometric mean values of C(max) and AUCs fell within the interval of 80-125%. Results from this PKs comparison of two different rFVIII products, using chromogenic substrate assay to measure FVIII:C, showed that ReFacto and Advate are bioequivalent to each other.

Transport of cosalane-a highly lipophilic novel anti-HIV agent-across caco-2 cell monolayers.

Cosalane is a potent inhibitor of HIV replication with activity against a broad range of viral targets. However, the oral bioavailability of this highly lipophilic compound is extremely poor (<1%). Also, cosalane accumulates in high concentration in the liver after intravenous administration, with clear resistance to hepatic metabolism. In the present study, the transcellular permeability of cosalane was examined using Transwell(R) filter as well as plastic-grown confluent Caco-2 cell monolayers. A cell-culture-based biophysical model was adopted to understand the interactions of protein binding, membrane partitioning, and aqueous solubility of cosalane in limiting transcellular flux of cosalane across Caco-2 cell monolayers. The transcellular permeability (P(app)) of cosalane was extremely low (4.494 x 10(-8) cm/s) and the effect of p-glycoprotein on the efflux of cosalane was negligible. A characteristic disparity exists between the kinetics of cosalane uptake from apical (AP) donor solution and efflux into basolateral (BL) receiver side. The AP uptake of cosalane was rapid, exhibiting exponential kinetics, and reached equilibrium within 60 min, whereas the concomitant appearance of the compound into the BL receiver side was slow but linear over time. Furthermore, the uptake of cosalane was significantly reduced in the presence of bovine serum albumin (BSA). In unidirectional efflux studies, AP efflux of cosalane was limited in the absence of BSA. Also, no detectable metabolites were found in Caco-2 cell incubations. In conclusion, the present study demonstrates that diffusion of cosalane across Caco-2 cell monolayers is extremely limited and kinetically regulated essentially by the equilibrium between protein-bound and free drug partitioning into cell membrane.

Pharmacokinetics, biliary excretion, and tissue distribution of novel anti-HIV agents, cosalane and dihydrocosalane, in Sprague-Dawley rats.

Cosalane and dihydrocosalane are potent inhibitors of HIV replication with a broad range of activity. The purpose of this study was to investigate: 1) the pharmacokinetic disposition of both cosalane and dihydrocosalane in male Sprague-Dawley rats, and 2) biliary excretion, enterohepatic circulation, and tissue distribution of cosalane after i.v. and/or oral administration. Animals were administered i.v. (10 mg/kg) cosalane or dihydrocosalane through a jugular vein to obtain plasma profiles. Dose dependence of cosalane was studied over a dose range of 1.0 to 10 mg/kg. The extent of enterohepatic recycling, biliary excretion, and tissue distribution were studied after i.v. administration. Both cosalane and dihydrocosalane exhibited a biexponential disposition with very long half-lives of 749 +/- 216 and 1016 +/- 407 min, along with very large volumes of distribution 23.1 +/- 4.4 and 24.4 +/- 2. 5 liter/kg, respectively. Both cosalane (nondetectable) and dihydrocosalane (<1%) showed very poor oral bioavailability. The biliary and renal excretions of cosalane were found to be negligible with no detectable metabolites either in urine or bile. After oral administration, more than 87% of the cosalane dose was excreted in the feces as the parent compound. Also, cosalane was sequestered significantly in liver with quantifiable levels in all tissues tested, even 48 h after the dose was administered. Therefore it was concluded that the poor oral bioavailability of cosalane may be due to its poor enterocytic transport coupled with sequestration in liver parenchymal cell membrane layers.

Disposition of cosalane, a novel anti-HIV agent, in isolated perfused rat livers.

Cosalane is a potent inhibitor of HIV replication with a broad range of activity. In this study, the hepatic disposition of cosalane was investigated with a noncirculating isolated perfused rat liver technique. When 6 microM cosalane was infused into livers from untreated rats, the drug was highly extracted by the liver (only 2. 5% of influent cosalane concentration appeared in the effluent perfusate). Pretreatment of rats with various inducers of cytochrome P-450 before perfusion neither altered the effluent cosalane concentration nor resulted in the appearance of detectable metabolites in the effluent perfusate or liver homogenates. Hepatic uptake of cosalane was negligible when the drug was infused in the presence of BSA, and infusion of albumin after cosalane resulted in a significant displacement of the drug into the effluent perfusate. Furthermore, permeabilization of perfused livers with digitonin significantly diminished effluent cosalane concentration while enhancing cosalane uptake by the liver. Based on our data, it appears that a significant proportion of cosalane does not penetrate the hepatocyte membrane and may accumulate in the lipid bilayer of the cell membrane. This finding supports the proposed mechanism explaining the antiviral effect of cosalane which stipulates that this compound appears to imbed perpendicularly in the lipid bilayer of the cell membrane and the viral envelope. Also, cosalane does not seem to be metabolized by the liver as evidenced by the lack of detectable metabolites in the effluent perfusate, liver homogenates, and liver microsomal incubations.

Synthesis, stereoselective enzymatic hydrolysis, and skin permeation of diastereomeric propranolol ester prodrugs.

Four diastereomeric propranolol ester prodrugs (1S2S, 1S2R, 1R2S, 1R2R) were synthesized by treating pure R- and S-propranolol hydrochloride with pure enantiomers R- and S-phenylbutyryl chloride. A HPLC technique using alpha-1 acid glycoprotein (chiral AGP) column was developed to study the racemization of propranolol enantiomers during synthesis and hydrolysis studies. A reversed phase HPLC method was also developed to simultaneously analyze propranolol and the ester prodrug. Hydrolysis of these esters was studied in different rat tissue homogenates, i.e., liver, intestine, plasma, skin, brain, and pure plasma cholinesterases, i.e., butyryl cholinesterase (EC 3.1.1.8) and acetyl cholinesterase (EC 3.1.1.7). In vitro percutaneous permeation studies across full thickness shaved rat skin were performed using standard side-by-side diffusion cells at 37 degrees C. The disappearance of the diastereomeric ester prodrugs in rat tissue homogenates followed apparent first-order kinetics and was stereoselective. The ratio of brain to plasma hydrolytic rate constants are 27.8, 5.58, 6.07, and 2.97 for 1S2S, 1R2R, 1R2S, and 1S2R esters, respectively. Hydrolysis of all four diastereomeric ester prodrugs was faster by acetyl cholinesterase than butyryl cholinesterase and is stereoselective. The permeability coefficients [Kp x 10(3) (cm h-1)] are 1.40 +/- 0.30, 1.41 +/- 0.27, 42.20 +/- 1.24, 29.26 +/- 3.41, 16.27 +/- 3.12, 12.99 +/- 2.84 for (R)-propranolol, (S)-propranolol, 1S2S, 1R2S, 1S2R, and 1R2R ester prodrugs, respectively. The results indicate that the 1R2S diastereomeric ester prodrug of propranolol shows greatest stability in liver and intestinal tissues while it exhibits fairly rapid conversion in plasma. The results also suggest the configuration on the second chiral carbon atom to be the determinant in the rate of hydrolysis of all the diastereomeric prodrugs in all biological media examined. The Kp of all four prodrugs markedly increased compared to that of the parent drug, with 1S2S showing a 30-fold increase in skin permeability, the highest among all four prodrugs.