David W. A. Bourne

Nano-advantage in Enhanced Drug Delivery with Biodegradable Nanoparticles: Contribution of Reduced Clearance

The aim of this study was to investigate the contribution of reduced apparent clearance to the enhanced exposure reported for biodegradable nanoparticles after extravascular and intravascular routes of administration. Plasma concentration profiles for drug and nanoparticle formulations after administration by intravenous, intraduodenal, and oral routes were extracted from the literature. Data were fit to pharmacokinetic models using BOOMER. The compartmental pharmacokinetic analysis of literature data for six drugs (camptothecin, 9-nitrocamptothecin, epirubicin, vinpocetine, clozapine, and cyclosporine) showed that the encapsulation of drug molecules in nanoparticles significantly reduced the apparent clearance and prolonged the apparent circulation half-life compared with those for the plain drug. Positively charged nanoparticles assessed in this study had lower apparent clearance, lower elimination rate constant values, and longer apparent circulation half-life than neutral and negatively charged nanoparticles. After oral administration, a reduction in apparent clearance contributed substantially to elevations in plasma drug exposure with nanoparticles. For the drugs and delivery systems examined, the nano-advantage in drug delivery enhancement can be explained, in part, by reduced clearance.

Impact of the CYP2C8 *3 polymorphism on the drug–drug interaction between gemfibrozil and pioglitazone

AIM The objective of this study was to determine the extent to which the CYP2C8*3 allele influences pharmacokinetic variability in the drug-drug interaction between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 substrate). METHODS In this randomized, two phase crossover study, 30 healthy Caucasian subjects were enrolled based on CYP2C8*3 genotype (n = 15, CYP2C8*1/*1; n = 15, CYP2C8*3 carriers). Subjects received a single 15 mg dose of pioglitazone or gemfibrozil 600 mg every 12 h for 4 days with a single 15 mg dose of pioglitazone administered on the morning of day 3. A 48 h pharmacokinetic study followed each pioglitazone dose and the study phases were separated by a 14 day washout period. RESULTS Gemfibrozil significantly increased mean pioglitazone AUC(0,∞) by 4.3-fold (P < 0.001) and there was interindividual variability in the magnitude of this interaction (range, 1.8- to 12.1-fold). When pioglitazone was administered alone, the mean AUC(0,∞) was 29.7% lower (P = 0.01) in CYP2C8*3 carriers compared with CYP2C8*1 homozygotes. The relative change in pioglitazone plasma exposure following gemfibrozil administration was significantly influenced by CYP2C8 genotype. Specifically, CYP2C8*3 carriers had a 5.2-fold mean increase in pioglitazone AUC(0,∞) compared with a 3.3-fold mean increase in CYP2C8*1 homozygotes (P = 0.02). CONCLUSION CYP2C8*3 is associated with decreased pioglitazone plasma exposure in vivo and significantly influences the pharmacokinetic magnitude of the gemfibrozil-pioglitazone drug-drug interaction. Additional studies are needed to evaluate the impact of CYP2C8 genetics on the pharmacokinetics of other CYP2C8-mediated drug-drug interactions.

Clinical and Medicoeconomic Impact of the Cyclosporine‐Diltiazem Interaction in Renal Transplant Recipients

The effect of the diltiazem‐cyclosporine interaction on cyclosporine pharmacokinetics, pharmacodynamics, and pharmacoeconomics was studied in 10 recipients of renal allografts. Each subject was studied while receiving diltiazem 60 mg twice/day and while not taking the drug. After achieving steady‐state conditions, cyclosporine and metabolite concentrations were determined in whole blood from samples drawn after the morning cyclosporine dose. After pharmacokinetic analysis, all patients were followed for 6 months during treatment with cyclosporine plus diltiazem or cyclosporine alone. Cyclosporine blood clearance decreased significantly after treatment with diltiazem (18.0–11.0 ml/minkg; p=0.008). The apparent volume of cyclosporine distribution also decreased significantly (4.26–2.62 L/kg; p<0.05). After 6 months, diltiazem had no effect on renal function indexes, and no apparent effect on immunosuppression. Alterations in cyclosporine clearance and apparent volume of distribution secondary to diltiazem result in dosage reduction and potential cost savings in transplant pharmacotherapy. The mean decrease in cyclosporine dosage requirements would produce a cost saving of

Regression of glioma tumor growth in F98 and U87 rat glioma models by the Nitrone OKN-007

1520 or 28% per patient per year.

Application of Physiologically Based Pharmacokinetic Models for Assessing Drug Disposition in Space

BACKGROUND Glioblastoma multiforme, a World Health Organization grade IV glioma, has a poor prognosis in humans despite current treatment options. Here, we present magnetic resonance imaging (MRI) data regarding the regression of aggressive rat F98 gliomas and human U87 glioma xenografts after treatment with the nitrone compound OKN-007, a disulfonyl derivative of α-phenyl-tert-butyl nitrone. METHODS MRI was used to assess tumor volumes in F98 and U87 gliomas, and bioluminescence imaging was used to measure tumor volumes in F98 gliomas encoded with the luciferase gene (F98(luc)). Immunohistochemistry was used to assess angiogenesis (vascular endothelial growth factor [VEGF] and microvessel density [MVD]), cell differentiation (carbonic anhydrase IX [CA-IX]), hypoxia (hypoxia-inducible factor-1α [HIF-1α]), cell proliferation (glucose transporter 1 [Glut-1] and MIB-1), proliferation index, and apoptosis (cleaved caspase 3) markers in F98 gliomas. VEGF, CA-IX, Glut-1, HIF-1α, and cleaved caspase 3 were assessed in U87 gliomas. RESULTS Animal survival was found to be significantly increased (P < .001 for F98, P < .01 for U87) in the group that received OKN-007 treatment compared with the untreated groups. After MRI detection of F98 gliomas, OKN-007, administered orally, was found to decrease tumor growth (P < .05). U87 glioma volumes were found to significantly decrease (P < .05) after OKN-007 treatment, compared with untreated animals. OKN-007 administration resulted in significant decreases in tumor hypoxia (HIF-1α [P < .05] in both F98 and U87), angiogenesis (MVD [P < .05], but not VEGF, in F98 or U87), and cell proliferation (Glut-1 [P < .05 in F98, P < .01 in U87] and MIB-1 [P < .01] in F98) and caused a significant increase in apoptosis (cleaved caspase 3 [P < .001 in F98, P < .05 in U87]), compared with untreated animals. CONCLUSIONS OKN-007 may be considered as a promising therapeutic addition or alternative for the treatment of aggressive human gliomas.

Incorporation, Release, and Effectiveness of Dexamethasone in Poly(Lactic-Co-Glycolic Acid) Nanoparticles for Inner Ear Drug Delivery

Exposure to weightlessness induces physiologic changes that may lead to pharmacokinetic and pharmacodynamic alterations of drugs administered to crew members in flight. Preliminary data from flight and ground‐based studies indicate that pharmacologically significant changes occur in the kinetics of medications given in weightlessness and in simulated microgravity (head‐down bed rest). Conducting flight studies on all available medications to identify the changes in their pharmacokinetic behavior in weightlessness is not feasible. An alternative approach for obtaining such information is to use computer simulations employing physiologically based pharmacokinetic (PBPK) models. Information thus obtained would be helpful in predicting the therapeutic effectiveness of medications in space, and also in developing plans for flight studies. This paper presents a brief review of relevant physiologic factors and pharmacokinetic implications of space flight, and includes a preliminary PBPK model for estimating plasma concentration‐time profiles of acetaminophen under different experimental conditions.

Using the Internet as a Pharmacokinetic Resource

Poly (D,L-lactide-co-glycolide) (PLGA) particles have been widely used as drug delivery carriers for a variety of payloads. Three forms of dexamethasone (DEX), namely, acetate, base, and phosphate, were incorporated into a PLGA matrix. First, we compared the drug loading efficiency and release kinetics of drug-loaded PLGA particles. Dexamethasone acetate (DEX-Ac) loaded particles exhibited a higher loading efficiency and a more linear release profile of drug as compared with the other forms of DEX particles. Also, we coincorporated oleic acid-coated superparamagnetic iron oxide nanoparticles (SPION) with DEX-Ac into PLGA submicron particles. No differences in size, zeta potential, drug loading, or release kinetics were found between particles prepared with and without SPION. Additionally, particles were applied to an in vitro cochlear, organotypic culture. DEX-Ac PLGA nanoparticles showed a protective effect against 4-hydroxynonenal induced hair cell damage. These results suggest a promising method for inner ear magnetic targeted treatment.

Magnetic Targeting of Therapeutics

SummaryThe Internet is an growing resource for scientific information, and includes information which can be useful to the pharmacokineticist. Once connected to the Internet there is a wide variety of information sources available. Collaboration with colleagues, research groups, discussion lists or news groups can be a valuable use of the Internet. Interactive discussions are possible using Internet Relay Chat or other conferencing software. There are a multitude of data, software and other information available via FTP, gopher or World Wide Web servers. This information may be exclusively research-oriented or more useful for instructional use, or suitable for both.

Physiological pharmacokinetic model of ceftriaxone disposition in the rat and the effect of caffeine on the model

Multiple formulations of nano-sized particles, capsules, dendrimers, lipids, ceramics and genetic materials are being investigated in multiple labs for delivery of therapeutic moieties to targeted tissues. Interest is driven by reducing health care costs while increasing therapeutic efficacy and cost of treatment. One technology, magnetic targeting, incorporates iron oxide nanoparticles, to target nanomedicine payloads, down the gradients of external magnetic fields. When iron oxide crystal domains are less than ∼20–40 nm, particles become superparamagnetic (SPION), that is exhibit no remanent induction but very high magnetic susceptibility in the presence of an external magnetic field. Thus, targeting can be vectored by magnetic lines of flux. Particles can be pulled out of the microcirculation and across membranes into tissues. Two target organs that can employ magnetic targeting are the heart (epicardium) and inner ear (cochlea).Copyright

Disposition of Aerosolized Liposomal Amphotericin B

A Physiologically based pharmacokinetic model was used to describe the distribution and elimination of ceftriaxone in the rat. To validate the practical application of the model, the effect of caffeine on the model was also examined. The model consisted of eleven compartments representing the major sites for ceftriaxone distribution including carcass which served as a residual compartment. Elimination was represented by renal and hepatic (metabolic biliary) excretion with GI secretion and re-absorption. The drug concentrations in most of the tissues were simulated using flow limited equations while brain levels were simulated using membrane limited passive diffusion distribution. The experimental data were obtained by averaging the concentration of drug in the plasma and tissues of five rats after i.v. injection of ceftriaxone 100 mg/kg without and with caffeine 20 mg/kg. The data for the amount of ceftriaxone excreted in urine and gut contents were used to apportion total body clearance. HPLC with UV detection was used for the assay with 0.1–0.2 μ g/ml sensitivity. The great majority of drug concentrations with and without caffeine show reasonably good agreements to the simulation results within 20%. The effect of caffeine on renal and hepatic clearances was apparent with 18.8% and 18.6% increase in the model values, respectively.