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Our previous studies suggested that both catechol O-methyl transferase (COMT) and glutathione S-transferase (GST) M1 and T1 genotypes are associated with breast cancer risk. Here we extended the studies to evaluate the potential combined effect of these genotypes in individual breast cancer risk. Incident breast cancer cases (n = 202) and controls (n = 299) with no previous cancer were recruited from three teaching hospitals in Seoul in 1996-1999. Information on putative risk factors was collected by interviewed questionnaire. PCR-based methods were used for the genotyping analyses. Odds ratios (ORs) and 95% confidence (CIs) intervals were estimated by unconditional logistic regression after adjustment for known or suspected risk factors of breast cancer. Among pre-menopausal women the low activity associated (COMT *L) allele containing genotypes and the GSTM1 null genotype posed increased risks of breast cancer with ORs of 1.7 (95% CI = 1.0 - 2.8) and 1.7 (95% CI = 1.0-2.8), respectively. A marginally significant effect of GSTT1 null genotype was also observed when the total study population was considered (OR = 1.3, 95% CI = 1.0-2.1). When the combined genotype effects were examined, the concurrent lack of GSTM1 and GSTT1 genes posed a more than 2-fold risk of breast cancer (OR = 2.2, 95% CI = 1.2-3.9); this effect was mainly attributable in pre-menopausal women (OR = 3.2, 95% CI = 1.5-7.2). Moreover, the breast cancer risk increased in parallel with the number of COMT , GSTM1 , and GSTT1 at-risk genotypes (p for trend = 0.003). This association was particularly clear in pre-menopausal women among whom combination of all three high-risk genotypes posed a 4.1-fold breast cancer risk (95% CI = 1.4-12.7) compared with pre-menopausal women without at-risk genotypes (p for trend = 0.001). The trend was more pronounced in women with BMI greater than 22 kg/m2 (p for trend0.001) and high-risk status of parity factor (nulliparous or women with the first full term pregnancy at age of over 25-year-old) (p for trend = 0.013). These results suggest the combined effect between reproductive factors and GSTM1, GSTT1 and COMT genotypes in human breast carcinogenesis.

We adopted an in vitro infective endocarditis model (IVIEM) to compare the efficacy of vancomycin (VAN), arbekacin (ABK), and gentamicin (GEN) alone or in combination. Using two strains of clinically isolated methicillin-resistant Staphylococcus aureus , one GEN susceptible (GS171) and one GEN resistant (GR153), fibrin clots were prepared and suspended in the IVIEM. Antibiotics were given as boluses every 6 h (q6h), q12h, or q24h or by continuous infusion with VAN, q12h or q24h with ABK, and q8h or q24h with GEN. For combination treatment, VAN q12h plus ABK q24h and VAN q12h plus GEN q24h were given. Fibrin clots were removed from each model at 0, 8, 24, 32, 48, and 72 h, and the bacterial densities were determined. The number of colonies within the fibrin clot was significantly decreased in all study groups compared with control groups ( P < 0.001). When VAN and ABK were administered alone, the number of colonies was significantly lower in GS171 than in GR153 by 8 h after administration ( P = 0.02) and was lowest in GS171 when ABK was administered q12h ( P = 0.01). At 72 h, ABK or VAN alone produced equivalent bacterial reductions regardless of dosing frequency and GEN resistance. In GR153, VAN plus ABK showed an additive effect till 24 h, although VAN plus GEN showed indifference. Our data suggest that ABK could be used as an alternative to VAN in GEN-resistant staphylococcal endocarditis. An additive effect was seen when VAN and ABK were used together in GEN-resistant strains until 24 h; however, further studies are warranted for the clinical application of this combination.

The pharmacokinetics of omeprazole and its metabolites in healthy subjects were evaluated to determine if a single dose of moclobemide inhibited CYP2C19 activity.Sixteen volunteers, of whom eight were extensive metabolizers (EM) and eight were poor metabolizers for CYP2C19, participated in two studies. Venous blood samples were collected for 24 h after oral ingestion of 40 mg omeprazole with or without 300 mg moclobemide coadministration. The pharmacokinetic change of omeprazole, omeprazole sulphone and 5-hydroxyomeprazole concentrations were assessed to test for an interaction between omeprazole and moclobemide.The coadministration of moclobemide in EMs approximately doubled the mean AUC (from 1834 to 3760 ng ml(-1) h) and C(max) (from 987 to 1649 ng ml(-1)) of omeprazole, and increased the AUC of omeprazole sulphone without changing AUC ratio of omeprazole to omeprazole sulphone. Moclobemide coadministration more than doubled the AUC ratio of omeprazole to 5-hydroxyomeprazole (from 2.5 to 5.3) in EMs, too. There was a significant decrease in Cmax and AUC of 5-hydroxyomeprazole in PMs but no significant changes were seen in the results for omeprazole and omeprazole sulphone AUCs.A single dose of moclobemide resulted in significant suppression of CYP2C19 activity in EMs. We conclude that physicians prescribing moclobemide should pay attention to its pharmacokinetic interactions even on the first day of coadministration with CYP2C19 substrates.

Vancomycin therapy has long been individualized through concentration monitoring. Because the therapeutic drug concentration monitoring (TDM) service is not available in all hospitals, ways to predict its area under the curve (AUC) using estimated creatinine clearance (CLcr) without drug concentration have been sought. More than 80% of vancomycin is eliminated via renal excretion and its clearance (CL) is known to be approximately 50-80% of measured glomerular filtration rate (GFR) [1]. Thus, an equation describing linear relationship between vancomycin clearance (CL) and CLcr may be used to predict vancomycin AUC without measuring its concentration.

Plasma ionized calcium (Ca(2+)) concentrations are tightly regulated in the body and maintained within a narrow range; thus it is challenging to quantify calcium absorption under normal physiologic conditions. This study aimed to develop a mechanistic model for the parathyroid hormone (PTH) response after calcium intake and indirectly compare the difference in oral calcium absorption from PTH responses. PTH and Ca(2+) concentrations were collected from 24 subjects from a clinical trial performed to evaluate the safety and calcium absorption of Geumjin Thermal Water in comparison with calcium carbonate tablets in healthy subjects. Indirect response models (NONMEM Ver. 7.2.0) were fitted to observed Ca(2+) and PTH data, respectively, in a manner that absorbed but unobserved Ca(2+) inhibits the secretion of PTH. Without notable changes in Ca(2+) levels, PTH responses were modeled and used as a marker for the extent of calcium absorption.

Jung-Shin Park, Jongtae Lee, Jeffrey Meyer, Palanichamy Ilankumaran, Seunghoon Han and Dong-Seok Yim* Department of Pharmacology, PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea, SK Biopharmaceuticals Co., Ltd., Seoul, Korea, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Canada, SK Life Science, Inc., NJ, USA *Correspondence: D. S. Yim; Tel: +82-2-2258-7327, Fax: +82-2-2258-7876, E-mail: yimds@catholic.ac.kr

A case-control study was performed to assess the potential influence of catechol O-methyl transferase (COMT) genotype on the risk of breast cancer in Korean women. One hundred and sixty-three histologically confirmed incident breast cancer cases and 163 age- and menopausal status-matched control individuals with no present or previous history of cancer were selected as study subjects. COMT genetic polymorphism was determined by gel electrophoresis after NlaIII enzyme digestion of amplified DNA. Odds ratios and 95% confidence intervals were estimated by unconditional logistic regression after adjustment for known or suspected risk factors of breast cancer. Women with at least one COMT lower enzyme activity associated allele (COMT-L) were at elevated risk for breast cancer (OR = 1.7, 95% CI = 1.04-2.78) compared with those homozygous for high enzyme activity associated COMT-H alleles. Among women with low (or = 23.1) body mass index the COMT-L allele containing genotypes posed a marginally significant increased risk of breast cancer compared to the COMT-HH genotype (OR = 1.8, 95% CI = 0.95-3.48). Women with at least one COMT-L allele who had experienced a full-term pregnancy when aged over 30 years or were nulliparous had 2.7-fold increased risk; however, this increase did not reach statistical significance (OR = 2.7, 95% CI = 0.64-11.35). Furthermore, never-drinking and never-smoking women with at least one COMT-L allele were at increased risk of breast cancer compared to those with COMT-HH genotype with ORs of 2.0 (95% CI = 1.23-3.38) and 1.7 (95% CI = 1.04-2.62), respectively. These results are consistent with studies showing that COMT genotype of lower enzyme activity might be related to increase in risk of breast cancer, and extend this finding to Korean women.

Results: All enrolled participants completed the study. The point estimates and 90 % confidence intervals of log transformed Cmax and AUClast of the test formulation in comparison to those of reference formulation were 0.9294(0.8353 - 1.0341) and 0.9415 (0.8869 - 0.9994) respectively. The analysis of variance showed no significant influences of formulation, sequence and period on the pharmacokinetic parameters. The frequencies of adverse events were not statistically different between the formulations. No serious adverse event was observed or reported.

Background: Levodropropizine is non-opioid agent whose peripheral antitussive action may result from its modulation of sensory neuropeptide levels. Currently, levodropropizine 60 mg is taken three-times daily. A controlled release formulation of levodropropizine (levodropropizine CR) 90 mg was developed, which can be taken twice daily. The aim of this study was to evaluate the safety and pharmacokinetic characteristics after multiple oral administrations of levodropropizine CR 90 mg tablets in healthy male volunteers. Methods: A randomized, open-label, cross-over study was conducted in 24 healthy male volunteers. Each subject received levodropropizine syrup 60 mg three times daily or levodropropizine CR 90 mg twice daily for 3 days. Blood samples for pharmacokinetic analysis were collected pre-dose and up to 24 hours on day 4. Pharmacokinetic analysis was conducted by non-compartmental method. Safety assessments including monitoring adverse events, laboratory tests, vital signs, physical examinations and ECGs were performed throughout the study. Results: A total of 20 male volunteers completed the study. The maximum steady-state plasma concentration (Css,max) of levodropropizine syrup and levodropropizine CR were 313.28 ng/mL and 285.31 ng/mL and time to reach Css,max (Tmax,ss) were 0.48 hr and 0.88 hr, respectively. The area under the concentration-time curve to the last measured concentration of two groups were 2345.36 hr × ng/mL and 2553.81 hr × ng/mL, respectively. There was no serious adverse event. Conclusion: Levodropropizine CR 90 mg tablet was safe and well-tolerated when administered twice daily for 3 days. No statistically significant differences were seen in Css,max and AUCss,24hr between the two formulations. This study provided pharmacokinetic evidences that the twice-daily dosing regimen of levodropropizine 90 mg may substitute the conventional 3-times-daily regimen of levodropropizine 60 mg.

Abstract 3076 Introduction: Maintenance therapy with hypomethylating agents (HMA) after HSCT is being suggested as potentially attractive approach to minimize relapse. Many studies reported the antileukemic and immunomodulatory effects of HMA with a favorable toxicity and a potential to expand the number of hematopoietic stem cells. Under the hypothesis that post-transplant maintenance therapy with decitabine (DAC) may reduce relapse rate, we designed a phase I clinical trial to determine the safe dose of DAC by an adaptive method using pharmacokinetic-pharmacodynamic (PK-PD) mixed effect modeling and simulation (M&S). Methods: Patients who received HSCT for higher-risk MDS and MDS/AML were eligible. The conditioning regimen was i.v. busulfan (6.4 or 12.8mg/m2) and fludarabine (150mg/m2). GVHD prophylaxis was cyclosporine or tacrolimus with methotrexate. ATG was administered to all patients. Patients in the disease remission with appropriate recovery of platelet count (PC>30,000/mm3) and absolute neutrophil count (ANC>1,000/mm3) without grade III/IV acute GVHD received DAC on day 42–90 post-transplant. For each subject, a designated dose of DAC was intravenously given for 5 consecutive days and repeated every 4 weeks up to 12 cycles. A cohort consisted of 3 patients where the same daily dose was given and the initial dose for the first cohort was daily 5 mg/m2. A total of 7 PK samples were collected up to 3 hours after the first dose. PC and ANC were monitored weekly as PD markers. After the 1st cycle, the dose for the next cycle was simulated in each patient with mixed-effect M&S using NONMEM, by which an adjusted dose was expected not to cause grade IV hematological toxicity (PC>25,000 or ANC>500) at the simulated lower limit of 50%. This M&S-guided dose calculation was continued until the cycle 4 and the dose at the 4th cycle was maintained fixed thereafter without further dose re-calculation unless evidences alarming dose adjustment occurred. The initial doses of the next cohorts were also determined by the M&S using the PK and PD data of previous cohorts. Results: Twenty one patients were enrolled and DAC was delivered in 13 patients whose median age was 49 years (19–65). All patients received pre-transplant HMA with DAC (n=7) or azacitidine (n=6) for higher-risk MDS. HMA responses at time of HSCT were 1 CR, 5, marrow CR, 3 stable disease, and 4 progressive disease including 3 MDS/AML. Intensive chemotherapy was given 2 MDS/AML and 1 achieved marrow CR. All patients received peripheral blood stem cells from siblings (n=7) or unrelated donors (n=6). Excluding 1 patient whose data was insufficient for PK/PD modeling, a total of 4 cohorts with 12 patients are under this study so far. Among the subjects, 5 found the maintenance dose for each of them while the others are still in the adjustment steps. ANC showed more sensitive decrease by DAC than PC and the criteria of ANC>500 was the dose-limiting factor in most patients. At the individual level, the predictive performance of our PK-PD model was satisfactory. When the doses were given without M&S individualization (all of the first cycles and arbitrarily-escalated cases at the 2nd cycle), grade IV hematological toxicity occurred 6 times compared to those with M&S-guided dose determination 40% vs. 6.7%). The initial dose was changed from 5 mg/m2/day to 4 (cohort 2), 5 (cohort 3) and 5.5 (cohort 4) as guided by the population PK-PD approach. Many patients showed increasing tendencies of both PC and ANC possibly due to the improvement of graft function; therefore, the dose required to achieve the target nadir was escalated by cycle. DAC-associated nonhematological toxicities were minimal and there was no increase in transplant-related toxicities including GVHD. Conclusion: Judging from the number of toxicity events and study progress, the PK-PD M&S approach might be a better choice to ensure safety in each individual and to adjust dose between cohorts compared to fixed-dose design such as modified Fibonacci method. However, our model has a limitation that the improvement of graft function was not taken into consideration due to the sparseness of individual data. It will be implemented in our final analysis using all the data from this study to recommend optimal maintenance dose. Currently, the optimal initial dose, 5 mg/m2/day, could be estimated by M&S approach when only the 1st cycle data of all the participants were used. Disclosures: Off Label Use: Maintenance therapy with decitabine after hematopoietic stem cell transplantation. Kim:Jassen: Honoraria, Research Funding.

We analyzed the pharmacokinetics of C3G on data from twelve subjects, after 2-week multiple dosing of black bean (Phaseolus vulgaris, Cheongjakong-3-ho) seed coat extract, using the mixed effect analysis method (NONMEM, Ver. 6.2), as well as the conventional non-compartmental method. We also examined the safety and tolerability. The PK analysis used plasma concentrations of the C3G on day 1 and 14. There was no observed accumulation of C3G after 2-week multiple dosing of black bean seed coat extract. The typical point estimates of PK were CL (clearance)=3,420 l/h, V (volume)=7,280 L, Ka (absorption constant)=9.94 h(-1), ALAG (lag time)=0.217 h. The black bean seed coat extract was well tolerated and there were no serious adverse events. In this study, we confirmed that a significant amount of C3G was absorbed in human after given the black bean seed coat extract.

Abstract 1642 Background: Advanced stage T-cell lymphomas usually follow aggressive clinical course and their treatment outcomes are worse than B-cell non-Hodgkin lymphoma. Furthermore, the optimal treatment regimen is still not established for these disease entities. Thus, cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOP-like regimens are still used as a primary treatment even though their efficacy is not satisfactory. This unmet need of T-cell lymphomas has required the development of more effective regimen. Thus, we incorporated an oral mTOR inhibitor, everolimus (RAD001, Afinitor®) into CHOP regimen to improve its efficacy. The mTOR complex is one of emerging targets in the lymphoma treatment because mTOR signal pathway is used by malignant cells to promote growth and survival. Previous studies demonstrated a single agent activity of mTOR inhibitor against relapsed or refractory lymphomas. Furthermore, several animal study results suggested that the mTOR inhibitor might enhance the effects of vincristine and cyclophosphamide when it was tried in combination with these drugs. Thus, we performed the phase I study to evaluate the feasibility and safety of everolimus plus CHOP chemotherapy for advanced stage, aggressive T-cell lymphomas. Methods: We enrolled patients with newly diagnosed T cell lymphomas including peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-negative anaplastic large cell lymphoma (ALCL) and cutaneous T-cell lymphoma (CTCL). Extranodal NK/T-cell lymphoma was excluded because it is resistant to anthracycline-based chemotherapy, and mycosis fungoides was also excluded due to its indolent nature. All patients were Ann Arbor stage III/IV and had adequate organ function. Patients received everolimus from day 1 to day 15 (once daily schedule of four dose levels, 2.5, 5, 7.5, and 10mg/dose) in addition to 750 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin, 1.4 mg/m2 vincristine on day 1 and 100 mg/day prednisolone on days 1 to 5. Six cycles of therapy administered every 21 days were planned. As a pharmacokinetic study, steady state trough concentrations of everolimus were measured at the end of cycle 1 and 2. All patients provided written informed consents and this trial was registered at www.ClinicalTrials.gov (NCT01198665). Results: Fifteen patients were enrolled between October 2010 and April 2011 including PTCL-NOS (n = 8), AITL (n = 4), ALCL (n = 1) and CTCL (n = 2). Ten patients presented as stage IV (66.7%) and the majority of patients showed serum LDH elevation (n = 13, 86.7%). Thus, the International Prognostic Index risk was dominantly high or high-intermediate (n = 9, 60.0%). There was no dose-limiting toxicity (DLT) at the level I (2.5mg/dose of everolimus) while one patient experienced hematologic DLT (grade IV thrombocytopenia) at the level II (5mg/dose). Thus, after patients were enrolled up to six at the level II, dose of everolimus was escalated to 7.5mg (level III). At the level III, two patients experienced DLT (grade IV thrombocytopenia and febrile neutropenia) among six patients enrolled. Therefore, the maximum tolerated dose for everolimus was determined as 5mg. In the evaluation of pharmacokinetic profile, there were no differences in the trough concentrations of everolimus between cycle 1 and 2 for all of these three dose groups. There was no dose-limiting non-hematologic toxicity in the all three dose levels. Although the main toxicity of everolimus was hematologic toxicity and it was overlapped with the toxicity of CHOP regimen, these hematologic toxicities were manageable. Among 15 patients, 14 patients responded to the treatment including 7 complete responses and 7 partial responses. However, five patients relapsed or progressed during follow-up. Conclusions: Everolimus can be safely combined with CHOP chemotherapy and constitutes an active regimen in advanced stage, aggressive T-cell lymphoma patients. The recommended dose for subsequent phase II study of everolimus plus CHOP is 5 mg/dose of everolimus once daily for 15 days as first-line treatment. Disclosures: No relevant conflicts of interest to declare.

The number of clinical trials sponsored by global pharmaceutical companies performed in countries other than the U.S. and Western Europe has been steadily increasing over the past decade. Among those emerging countries, Korea deserves attention for its rapid growth in the number of trials and sites. As of 2009, Korea was ranked the tenth country in the number of clinical trials registered at http://clinicaltrials.gov. This is remarkable growth given that it was not included in the top 30 countries in 2005. High population density, qualified medical professionals, regulatory changes including Investigational New Drug-New Drug Application (IND/NDA) separation, acceptance of International Conferences on Harmonization-Good Clinical Practices (ICHGCP) by Korea Food&Drug Administration (KFDA), and governmental policies to boost clinical trials were the most influential factors that caused such an outstanding achievement. The Korean National Enterprise for Clinical Trials (KoNECT), an organization founded to lead initiatives to improve the milieu for clinical trials, has been playing a pivotal role in the steering of 15 regional clinical centers designated by the government. Based upon improvements in infrastructure so far, diversity in therapeutic areas and the proportion of early phase trials are expected to grow. Korea has grown to be one of the major countries in the clinical trial market, which was made possible by the cooperation of industry, academia and government. Further investment and efforts to solve current challenges will allow such growth to continue into the next decade.

Background To develop a model describing the circadian rhythm of the 24-hour ambulatory blood pressure monitoring (ABPM) measured diastolic blood pressure (DBP) in patients with mild to moderate essential hypertension when no drug is present. Methods 3,771 ABPM measurements from 107 hypertensive patients in a randomized placebo-controlled study of an antihypertensive agent, assigned to the placebo group (n=24, 3 occasions) or in the placebo run-in period (n=83), were analyzed by nonlinear mixed effects regression using NONMEM. FOCE with interaction was the estimation method. Results The final model was a two-cosine term model (24- and 12-hour cycles) having phase shift on clock time, with interindividual variability on the 24-hour rhythm adjusted mean, the amplitudes of the cosine terms, phase shift, and clock time. Interoccasion variability was also included on the 24-hour rhythm adjusted mean, the amplitude of the cosine term by 24-hour cycle and the clock time. The population standard of the 24-hour rhythm adjusted mean was 95.6 mmHg[95% CI: 93.5–97.7] and its interindividual and interoccasion variability were 9.2 CV%[6.2–12.1] and 3.2 CV%[0.6–5.7], respectively. The residual error was 7.48 mmHg. Conclusions A two-cosine model was able to characterize the circadian rhythm of ABPM measured DBP in this patient population. This model can be used as the baseline model to characterize the exposure-response relationship of antihypertensive agents. Clinical Pharmacology & Therapeutics (2005) 77, P57–P57; doi: 10.1016/j.clpt.2004.12.109

Objective To compare the time courses of concentrations between etanercept 0.8 mg/Kg once weekly and 0.4 mg/Kg twice weekly subcutaneous (SC) dosing in pediatric patients with JRA. Methods A Monte Carlo clinical trial simulation experiment was conducted to compare the PK profiles of 200 pediatric patients with JRA who randomly received either etanercept 0.4 mg/Kg SC twice weekly or 0.8 mg/Kg once weekly for 12 weeks. The population PK parameters and covariate distribution model derived from 69 JRA patients (age: 4-17), enrolled in a 3–month, PK incorporated, double-blind randomized phase III study, were used for simulation of 100 replicates with Pharsight Trial Simulator® (Pharsight Co., ver. 2.1.2, Mountain View, California). The parameter uncertainties were also incorporated. Results The mean±standard deviation values of simulated peak concentrations for 0.8 mg/kg once weekly dosing and 0.4 mg/kg twice weekly dosing were almost identical (2.92±1.41 mg/L and 2.62±1.23 mg/L, respectively). Trough concentrations during 0.8 mg/kg once weekly dosing (1.58±1.07 mg/L) is also comparable to those during 0.4 mg/Kg twice weekly dosing (1.92±1.09 mg/L). Conclusion This simulation study confirmed that 0.8 mg/Kg once weekly and 0.4 mg/Kg twice weekly SC regimen of etanercept will yield an overlapping steady-state time-concentration profile and are expected to yield equivalent clinical outcomes. Clinical Pharmacology & Therapeutics (2004) 75, P53–P53; doi: 10.1016/j.clpt.2003.11.201

Purpose To develop a systematic approach to identify and model the source of nonlinearity, detected as non-constant AUC/dose and Cmax/dose ratios, observed in PK analyses of ascending dose exposures (6–100 mg) of talampanel, an innovative antiepileptic drug. Methods: Graphical evaluations of partial-AUC/dose ratios from a 4-arm single dose-escalation PK study (n=24), were followed by population PK analyses (NONMEM) using model discrimination criteria to identify the likely source of nonlinearity. Results: Graphical patterns of partial AUC/dose and Cmax/dose ratios revealed greatest non-linearity in the early post-dose time period, leading to the assumption that absorption is the most probable source of nonlinearity. Saturable first-pass bioavailability (F) was modeled as an asymptotic function of dose (F=Dose/(Kd+Dose). A parallel zero-/first-order absorption model coupled with a 1-compartment linear model adequately described the entire PK profile of talampanel. Kd (dose yielding 50% F) was 4.7 mg (intersubject variability of F=77%). A similar model was evaluated using Michaelis-Menten elimination, but was rejected due to a Km estimate 4–5 times higher than the highest Cmax, and little improvement of model fitting criteria (decreased objective function value, diagnostic plots). Conclusion: Graphical analyses of dose normalized AUC and Cmax values, coupled with population PK model testing can be used to identify and model the source of nonlinearity observed in PK analysis. Clinical Pharmacology & Therapeutics (2004) 75, P90–P90; doi: 10.1016/j.clpt.2003.11.346