Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 4 uppsatser.

Background The lack of methadone pharmacokinetic data in children and neonates restrains dosing to achieve the target concentration in these populations. A minimum effective analgesic concentration of methadone in opioid naïve adults is 0.058 mg·l-1, while no withdrawal symptoms were observed in neonates suffering opioid withdrawal if plasma concentrations of methadone were above 0.06 mg·l-1. The racemate of methadone which is commonly used in pediatric and anesthetic care is metabolized to 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP). Methods Data from four studies (age 33-week PMA-15 years) were pooled (n = 56) for compartment analysis using nonlinear mixed effects modeling. Parameter estimates were standardized to a 70-kg person using an allometric model approach. Investigation was made of the racemate and metabolite (EDDP and EMDP) dispositions. In addition, neonatal data (n = 7) allowed further study of R- and S-enantiomer pharmacokinetics. Results A three-compartment linear disposition model best described the observed time-concentration profiles with additional compartments for metabolites. Population parameter estimates (between-subject variability) were central volume (V1) 21.5 (29%) l·70 kg-1, peripheral volumes of distribution V2 75.1 (23%) l·70 kg-1 and V3 484 (8%) l·70 kg -1, clearance (CL) 9.45 (11%)l·h-1·70 kg-1, and intercompartment clearances Q2 325 (21%) l·h -1·70 kg-1 and Q3 136 (14%) l·h -1·70 kg-1. EDDP formation clearance was 9.1 (11%) l·h-1·70 kg-1, formation clearance of EMDP from EDDP 7.4 (63%)l·h-1·70 kg-1, elimination clearance of EDDP was 40.9 (26%) l·h-1·70 kg-1 and the rate constant for intermediate compartments 2.17 (43%) h-1. Conclusions Current pharmacokinetic parameter estimates in children and neonates are similar to those reported in adults. There was no clearance maturation with age. Neonatal enantiomer clearances were similar to those described in adults. A regimen of 0.2 mg·kg-1 per 8 h in neonates achieves a target concentration of 0.06 mg·l-1 within 36 h. Infusion, rather than intermittent dosing, should be considered if this target is to be achieved in older children after cardiac surgery.

Methadone hydrochloride is an old drug that has been in vogue off and on. It has complex pharmacodynamics and can be potentially fatal in inexperienced settings. Drug switching from an opioid to methadone or vice versa requires knowledge of equianalgesic dosing. It is critical when using the drug to monitor for signs and symptoms of toxicity so that overdosing or toxicity can be identified in a timely manner. This review discusses these important topics so that methadone can be used safely and effectively.

Cyclosporine is used in veterinary medicine to treat a number of inflammatory and immune-mediated conditions, however firm oral dosing protocols have yet to be established in the dog. Traditionally a pharmacokinetic approach, through measurement of blood drug concentrations, has been the primary method of establishing if the given dose is effectively suppressing the immune system. However, there is some debate over how well blood drug concentrations correspond to immunosuppression, since individuals can vary in response to the same drug concentration. Our research group believes that a pharmacodynamic approach could alternatively be used to accurately determine cyclosporine dosages in individual patients since this will give a measurement of the immune system’s response to the drug, rather than simply how the body is processing it. This method will give a more accurate assessment of the patient’s immune system, and allow for better immunosuppressant therapy. The objective of this thesis was to develop a quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay that could reliably predict patient outcome during cyclosporine treatment. This assay would essentially work as a diagnostic tool that clinicians can use to help determine if they were using an appropriate cyclosporine dose for their patients. The assay measures cytokine expression of activated T cells, which are the target cell for the active metabolite of cyclosporine. Our objectives were achieved, firstly, through validation of the assay. Since this assay will be used by clinicians throughout the nation, we first established if shipping conditions affected the sample, and therefore assay results. Once the effect of sample storage time and temperature were determined, optimal sample collection timing was established. Finally, cytokine levels were measured in samples from clinical cases and healthy control dogs to examine the difference in cytokine expression between these two groups. An effective and reliable treatment method for cyclosporine has yet to be established in the dog; therefore the results of this thesis will lead to better therapeutic monitoring and more efficient use of cyclosporine therapy in canine patients.

No / Background: AQ4N (1,4-bis[[2-(dimethylamino)ethyl] amino]-5,8-dihydroxyanthracene-9, 10-dione bis-N-oxide dihydrochloride) is a prodrug which is selectively activated within hypoxic tissues to AQ4, a topoisomerase II inhibitor and DNA intercalator. Patients and methods: In the phase I study, 22 patients with oesophageal carcinoma received an i.v. infusion of AQ4N (22.5¿447 mg/m2) followed, 2 weeks later, by further infusion and radiotherapy. Pharmacokinetics and lymphocyte AQ4N and AQ4 levels were measured after the first dose. At 447 mg/m2, biopsies of tumour and normal tissue were taken after AQ4N administration. Results: Drug-related adverse events were blue discolouration of skin and urine, grade 2¿3 lymphopenia, grade 1¿3 fatigue, grade 1¿2 anaemia, leucopenia and nausea. There were no drug-related serious adverse events (SAEs). Three patients had reductions in tumour volume >50%, nine had stable disease. Pharmacokinetics indicated predictable clearance. Plasma area under the curve (AUC) at 447 mg/m2 exceeded AQ4N concentrations in mice at therapeutic doses and tumour biopsies contained concentrations of AQ4 greater than those in normal tissue. Tumour concentrations of AQ4 exceeded in vitro IC50 values for most cell lines investigated. Conclusions: No dose-limiting toxic effects were observed and a maximum tolerated dose was not established. Tumour AQ4 concentrations and plasma AUC at 447 mg/m2 exceeded active levels in preclinical models. This dose was chosen for future studies with radiotherapy.

No description available.

EGFR inhibitors, such as gefitinib, are examples of targeted anticancer drugs whose drug sensitivity is related to gene mutations that adds a pharmacogenetic [PG] dimension to any pharmacokinetic [PK] and pharmacodynamic [PD] analysis. The goal of this project was to characterize the PK/PD properties of gefitinib in tumors and then apply these results to design rational drug design regimens, and provide a foundation for future studies with EGFR inhibitors. Progressions of in vitro and in vivo studies were completed to understand the PK and PD behavior of gefitinib. In vitro cytotoxicity assays were first conducted to confirm the gefitinib sensitivity differences in a pair of human glioblastoma cell lines, LN229-wild-type EGFR and LN229-EGFRvIII mutant, an EGFR inhibitor-sensitizing mutation. Subsequent in vitro PD studies identified phosphorylated-ERK1/2 (pERK) as a common PD marker for both cell lines. To describe the most salient features of drug disposition and dynamics in the tumor, groups of mice bearing either subcutaneous LN229-wild-type EGFR or LN229-EGFRvIII mutant tumors were administered gefitinib at doses of 10 mg/kg intravenously (IV), 50 mg/kg intraarterially (IA) and 150 mg/kg orally (PO). In each group, gefitinib plasma and tumor concentrations were quantitated, as were tumoral pERK. Hybrid physiologically-based PK/PD models were developed for each tumor type, which consisted of a forcing function describing the plasma drug concentration-profile, a tumor compartment depicting drug disposition in the tumor, and a mechanistic target-response PD model characterizing pERK in the tumor. Gefitinib showed analogous PK properties in each tumor type, yet different PD characteristics consistent with the EGFR status of the tumors. Using the PK/PD model for each tumor type, simulations were done to define multiple-dose regimens for gefitinib that yielded equivalent PD profiles of pERK in each tumor type. Based on the designed PK/PD equivalent dosing regimens for each tumor type, gefitinib 150 mg/kg PO qd × 15 days and 65 mg/kg PO qd × 15 days multiple-dose studies were conducted in wild-type EGFR and EGFRvIII mutant tumor groups, respectively. In each tumor group, gefitinib plasma and tumor concentrations were measured on both day 1 and day 15, as were tumoral amounts of pERK. Different from single-dose model simulations, gefitinib showed nonlinear PK property in the wild-type tumor due to the down-regulation of membrane transporter ABCG2. Moreover, acquired resistance of tumoral pERK inhibition was observed in both tumor types. Nevertheless, gefitinib had an analogous growth suppression action in both tumor groups, supporting the equivalent PD dosing strategy. Overall, single-dose gefitinib PK/PD investigations in a pair of genetically distinct glioblastomas facilitated the development of hybrid physiologically-based PK/PD models for each tumor type, and further introduced a novel concept of PK/PD equivalent dosing regimens which could be applied in novel drug development paradigms. Preliminary multiple-dose gefitinib studies revealed more complex PK/PD characteristics that needed to be further explored. / Pharmaceutics

Master of Science / Department of Clinical Sciences / Elizabeth G. Davis / Objective: To determine pharmacokinetic and pharmacodynamic properties of oral dexamethasone solution and powder compared to intravenous dexamethasone solution in healthy horses. Animals: 6 horses, 13-27 years if age, 385-630 kg Procedures: In a randomized, cross-over block design six healthy adult horses each received the following treatments 1) dexamethasone solution IV 0.05 mg/kg, 2) dexamethasone solution orally (PO) 0.05 mg/kg, and 3) dexamethasone powder PO 0.05 mg/kg all in the fed and fasted state. Each horse acted as an untreated control as secretion of cortisol was monitored for normal circadian rhythm. Quantification of plasma dexamethasone concentration and serum cortisol activity was determined by LC/MS and chemiluminescent enzyme immunoassay, respectively. Results: Each horse exhibited a circadian rhythm in cortisol secretion; however there was variation present between each horse. Mean cortisol concentrations at 6:00 AM and 8:00 AM were significantly higher than concentrations at 8:00 PM and 10:00PM. Cortisol concentrations were significantly less than base-line starting 1 hour post-administration of dexamethasone through 72 hours for the fasted treatment groups, and 2 hours through 48 hours for the fed groups. Pharmacokinetic modeling resulted in a two compartment model for the IV administration with elimination from the central compartment, and a one compartment model for orally administered dexamethasone. Oral, fasted, compounded powder achieved a significantly higher maximum concentration (Cmax) than both fasted and fed oral dexamethasone solutions. The AUC0inf for the orally administered compounded powder was significantly different when comparing fasted versus fed treatment groups. Bioavailability ranged between 33% and 70% among treatment groups, but due to the high variability there was not a significant difference. Conclusions and Clinical Relevance: Hospitalization of the horses did not have an effect on their circadian rhythm of cortisol secretion. Oral and intravenous administration of dexamethasone resulted in adrenal suppression with cortisol concentrations returning to base-line 48-72 hours post-administration. Although bioavailability was variable cortisol suppression was similar among all treatment groups. The variability in oral absorption will need to be taken in to account for oral dosing of dexamethasone.

The presence of many human pharmaceuticals in the aquatic environment is now a worldwide concern and yet little is known of the chronic effects that these bioactive substances may be having on aquatic organisms. This study used mammalian pharmacodynamics to predict the mode of action of the 13-blocker, propranolol, on fish, in order to identify chronic effects in fathead minnows. β-blockers target β1- and β2-adrenergic receptors in humans and hence these receptors were characterised in the fathead minnow. It was found that fish possess β1- and β2-ARs that are structurally very similar to their mammalian counterparts. Further, the distributions of these two β-ARs in various organs of the fathead minnow were similar to those in mammals. Pair-breeding assays were conducted, in which fathead minnows were exposed to various concentrations of propranolol. To discover whether β-ARs had been up or down regulated by propranolol, molecular analysis was conducted on different tissues of the exposed fish using real-time polymerase-chain reactions (RT-PCR). Exposure of fathead minnows to propranolol caused acute toxicity at 10 mg/L. Propranolol caused a statistically significant decrease in reproduction at 1.0 mg/L, dose-related decreases in male weight, condition index and fatpad weight, and a dose-related increase in female GSI. Molecular analysis of βl- and β2-AR expression levels revealed a dose-related decrease in β2-AR expression in fathead liver and heart. LOEC and NOEC values were 0.1 mg/L and 0.01 mg/L, respectively. Propranolol plasma concentrations in fish exposed to water concentrations of 0.1 and 1.0 mg/L were greater than the human therapeutic concentration and hence these data very strongly support the fish plasma model proposed by Huggett et al. (2001).

Master of Science / Department of Clinical Sciences / James K. Roush / Hydrocodone and tramadol are opioid analgesics. No studies have been performed to evaluate the clinical efficacy or pharmacokinetics of hydrocodone/acetaminophen and tramadol in a heterogenous population of dogs. The efficacy of tramadol in dogs has been questioned based on previous pharmacokinetic data. The objectives of this study were to evaluate the analgesic effects of hydrocodone/acetaminophen and tramadol measured by a success/failure model and to determine the pharmacokinetic profile of each drug following the second oral drug dose administration. Fifty client-owned dogs presenting for routine tibial plateau leveling osteotomy were randomized to receive either oral hydrocodone/acetaminophen or tramadol in the postoperative period. A blinded investigator using a modified Glasgow Composite Measure Pain Scale scored each animal. Treatment failures were recorded and compared statistically for differences between the two groups. Blood sampling for pharmacokinetic analysis was initiated after the second oral dose. Mean [plus or minus] SE dose of hydrocodone/acetaminophen administered was 0.5 [plus or minus] 0.04 mg/kg and 16.6 [plus or minus] 1.41 mg/kg for hydrocodone and acetaminophen, respectively. Mean [plus or minus] SE dose of tramadol administered was 5.91[plus or minus] 0.61 mg/kg. The terminal half life, maximal serum concentration (Cmax) and time to maximal serum concentration (Tmax) for tramadol were approximately 1.56 hours, 155.6 ng/mL and 3.90 hours, respectively. Plasma concentrations of the active metabolite O-desmethyltramadol (M1) were low. For hydrocodone, the Cmax and Tmax were approximately 7.90 ng/mL and 3.47 hours, respectively. Plasma concentrations of hydromorphone were low after oral hydrocodone administration. Eighteen of 48 (37.5%) dogs required additional rescue analgesic therapy. This included 10 dogs in hydrocodone group and 8 dogs in the tramadol group (p=0.628). In a group of postoperative patients, no difference in pain scoring could be detected in hydrocodone/acetaminophen and tramadol groups. The pharmacokinetics of tramadol and metabolites were similar to previous studies. Wide variations existed in tramadol drug concentrations and the effects of tramadol are likely independent of the μ-opioid receptor. There is poor metabolism of hydrocodone to hydromorphone in dogs, however, efficacy may be achieved through hydrocodone. The analgesic efficacy of tramadol, 5-7 mg/kg PO q 8 h, and hydrocodone, 0.5 mg/kg PO q 8 h, should be assessed further prior to widespread use in canine postoperative patients.