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Background: Despite rifampicin and ethambutol being widely used to treat patients with tuberculosis, reports of potentially lethal overdoses of these drugs are rare. The toxic effects of rifampicin become apparent at doses of 9–12 g, and become potentially fatal at doses over 14 g. Case presentation: We describe a case of severe rifampicin (18 g) and ethambutol (25 g) poisoning that was successfully managed using hemoperfusion (HP) and hemodiafiltration (HDF) in conjunction with serum blood drug concentration monitoring. A 57-year-old female was rushed to the emergency room of Shenzhen Third People's Hospital (China) 4 hours after she ingested 120 tablets of rifampicin (18 g) and 100 tablets of ethambutol (25 g). After emergency symptom treatment, she was transferred to a ward where she presented in an irritable state, with orange–red skin and mucus membrane discoloration and slight yellowing of the sclera. The patient’s serum levels of rifampicin (177.2 mg/L), desacetylrifampicin (194.40 mg/L), and ethambutol (13.44 mg/L) were determined. After three cycles of HP and HDF, her serum drug levels had declined to within a normal range, and the color of her skin and mucosa gradually returned to normal. She was discharged from the hospital after a 4-day stay. Ten days after discharge, her follow-up bloodwork indicated normal liver and kidney functioning. Conclusions: HDF and HP are effective at clearing toxic levels of rifampicin. Serum drug concentration monitoring helps accurately guide drug poisoning treatment.

Aim: The dose of digoxin is often difficult to be determined precisely. The aim of this study was to retrospectively investigate the effect of blood biochemical indexes on the serum concentration of digoxin. Materials & methods: We collected the data of hospitalized patients treated orally with digoxin in Nanjing Drum Tower Hospital (Nanjing, China) from 2016 to 2018. Descriptive statistics was used to analyze the patients’ comprehensive condition. Results: A total of 425 patients were included in the study. Through analysis, nine factors were included in the regression model of the serum concentration of digoxin, and this regression model showed good predictive performance (r2 = 0.83138; p

OBJECTIVES: There is evidence to suggest that higher serum concentration of carotenoids is protective of osteoporosis, although studies have shown inconsistent findings. The majority of studies on serum carotenoids and bone have been conducted in predominantly non-Hispanic white populations. This study examined the relationship between serum total carotenoids and bone mineral density (BMD) and odds of osteoporosis among Puerto Rican older adults. METHODS: Data are from the Boston Puerto Rican Osteoporosis Study, a prospective cohort of Puerto Rican adults aged 47 to 79 y (n = 907). Serum total carotene (ug/dL) concentration was measured by fasting blood sample at baseline and 2-year follow-up. A cumulative average of the two measures was calculated. BMD (g/cm2) at the hip and lumbar spine sites were measured using dual x-ray absorptiometry. Multivariable analysis of covariance models tested associations between serum total carotenoids and BMD outcomes and multivariable logistic regression models examined associations with odds of osteoporosis. Models were adjusted for age, height, estrogenic (male, non-menopausal or taking hormone replacements, no estrogen) status, BMI, alcohol use, smoking status, calcium intake, and serum vitamin D and triglycerides. RESULTS: Participants were primarily female (72.1%), mean age: 59 years ± 7.4 and mean serum carotenoids: 93 ug/dL ± 34.2. Serum total carotenoids were not associated with BMD at the trochanter (β = 0.16 ± 0.13), femoral neck (β = 0.09 ± 0.13), total hip (β = −0.46 ± 0.18), or lumbar spine (β = 0.11 ± 0.14) (P = 0.16–0.50). Further, there was no association between serum carotenoids and odds of osteoporosis after adjusting for potential confounding (OR = 1.00, 95%CI: 0.99, 1.01). CONCLUSIONS: These findings suggest that dietary factors other than total carotenoids may be more important for bone health among Puerto Rican adults. Further research is needed to confirm these results. Investigation of individual dietary carotenoids may provide additional insight into the associations with bone in this population. FUNDING SOURCES: NIH (P01 AG023394, P50 HL105185, R01 AG027087). SEN is supported by K01 AR067894.

Introduction Pacemakers are frequently needed due to a high prevalence of conduction disease in mutated ATTR amyloidosis (mATTR). We aimed to identify the variables associated with the need of pacemaker implantation in this population. Methods We retrospectively studied 255 patients with suspicion of heart involvement of mATTR observed at our cardiology clinic during the last year. Clinical and outcome data were retrieved by chart review. We have defined the need for pacemaker implantation as: 1) the formal guidelines indications or 2) Ventricular pacing >10% in patients who had prophylactic pacemaker implantation prior to liver transplantation (LT). This way, we have defined 3 different groups: group 1: patients with no evidence of conduction disease; group 2: patients with conduction disease, but no formal indication for pacemaker implantation; and group 3: patients with formal indication for pacemaker implantation or ventricular pacing >10% in patients who had prophylactic pacemaker implantation prior to hepatic transplantation. Results We included 255 patients (50±14 years, 53% male, 52.5% treated with tafamidis and 27% had prior LT, and 10% with atrial fibrillation), 43.3% with no evidence of conduction disease, 32.3% with conduction disease, but no formal indication for pacemaker implantation and 24.4% with formal indication for pacemaker implantation. Patients with formal indication for pacemaker implantation were older, with longer duration of neurologic manifestations, with higher concentration of both Troponin T and NT-proBNP and with higher number of organs affected. In multivariate analysis, longer duration of neurologic manifestations (OR 1.090 – 95% IC: 1.036–1.145, p-value 0.001), Left ventricular (LV) maximal wall thickness (OR 1.230 – 95% CI: 1.070–1.414, p-value 0.004), neurologic staging (OR 3.420 – 95% CI: 1.443–8.104, p-value 0.005) and higher number of organs affected (OR 1.719 – 95% CI: 1.218–2.424, p-value 0.002) all showed to be independent predictors of the need for pacemaker implantation, in contrast to LV ejection fraction and serum concentration of Troponin T and NT-proBNP. We've also found a statistical significant association between conduction disease and ophthalmic manifestations. Conclusions Our findings suggest that the need for pacemaker implantation in patients with mATTR is closer linked to the duration, severity and affected number of organs than to cardiac biomarkers or echocardiographic findings. Funding Acknowledgement Type of funding source: None

Background Posaconazole (PCZ) is used prophylactically to prevent invasive fungal infections (IFIs) in patients with hematological malignancies. Objective To evaluate the cut-off serum concentration of PCZ for successful IFI prophylaxis in Chinese subjects. Patients and Methods A total of 74 patients treated with induction chemotherapy (n = 10) and allogeneic hematopoietic stem cell transplantation (HSCT) (n = 64), who received PCZ prophylactically as an oral suspension for >7 days, were included in the study. Clinical, radiological, microbiological culture results, and treatment responses were analyzed and drug concentration assays performed. Results The overall incidence of possible, probable, and proven IFIs was 13.5% (10/74), with five patients in the chemotherapy group and five in the HSCT group. The PCZ serum concentration in most patients (54/63) was in the range of 0.25–1.0 μg/ml, and this concentration range was significantly associated with the success rate of PCZ prophylaxis. A cut-off value of 0.47 μg/ml can be considered as an evaluation index for PCZ prophylaxis. Taking a proton pump inhibitor (PPI) would reduce the PCZ blood concentration, but not affect the IFD breakthrough point. PCZ treatment for hematopoietic malignancy or HSCT patients with a serum concentration of PCZ < 0.47 μg/ml were risk factors for PCZ prophylaxis of IFIs, determined by univariable and multivariable regression analyses. Conclusion The serum concentration of PCZ was related to the incidence of IFIs and a serum concentration of >0.47 μg/ml is highly recommended to avoid IFIs after chemotherapy or HSCT. Clinical Trial Registration Chinese Clinical Trial Registry: ChiCTR1900026294.

OBJECTIVES: Folate, or folic acid, is a water-soluble B vitamin that plays a role in single carbon transfer reactions, which are involved in the synthesis and metabolism of nucleotides and amino acids. It has been established that adequate folic acid intake helps decrease the prevalence of neural tube defects during conception and early pregnancy. The objective of this study was to assess the bioavailability of folic acid from Prenatal Multi Gummies and Folic Acid tablets in women of childbearing age. METHODS: Eleven healthy, adult, premenopausal women of childbearing age (18–44 years) were recruited for a single-blind, randomized, crossover study. Each participant was randomly assigned to receive a single dose (2 gummies or 2 tablets) of Prenatal Multi Gummies or Folic Acid tablets (containing ∼800 µg folic acid) and then crossed over to receive the other study product after a wash-out period of ∼7 days. The study product was consumed along with a low folic acid breakfast meal. Blood samples were collected for the analysis of serum folate at t = −0.5, 1, 2, 4, 6 and 8 hours where t = 0 is the time of study product consumption. RESULTS: The mean serum folate total area under the curve (AUC(0–8 hours)) was 239.67 ± 24.50 h × ng/mL for the Prenatal Multi Gummies and 255.23 ± 30.17 h × ng/mL for the Folic Acid tablets. For both study products, the dose-adjusted net incremental AUC was significantly greater than 0 h × ng/mL (P ≤ 0.001). The maximum serum folate concentration (C(max)) was 47.69 ± 5.65 ng/mL for the Prenatal Multi Gummies and 52.45 ± 5.86 ng/mL for the Folic Acid tablets, and the median time to maximum serum concentration (T(max)) was 1.00 h for each product (interquartile limits for both included 1.00 to 1.08 hours). CONCLUSIONS: In conclusion, folic acid contained in the Prenatal Multi Gummies and Folic Acid tablets was absorbed from both the Prenatal Multi Gummies and the Folic Acid tablets. FUNDING SOURCES: This study was funded by Pharmavite LLC.

Background Vancomycin dosing guidelines recommend loading doses (LDs) (25–30 mg/kg TBW), and a maintenance regimen, usually started after a time period equal to the dosing interval. Studies of vancomycin exposure and nephrotoxicity conclude that a 0 to 24-hour area under the serum concentration–time curve (0–24AUC) > 677 mg-hour/L results in a 3- to 4-fold increased risk of nephrotoxicity (Zasowski EJ, Antimicrob Agents Chemother 2018). For vancomycin LDs we compare the calculated LD and the maintenance dose, and delay initiation of the maintenance regimen when the LD exceeds the daily maintenance dose by > 50%. This study assessed the pharmacokinetic outcomes from this technique. Methods We retrospectively reviewed 68 consecutive adult patients receiving therapeutic doses of vancomycin. Patient age, sex, height, weight, serum creatinine, and indication were used to calculate the daily dose/intervals for a steady-state 24-hr AUC of 400 or 600 mg-hour/L. The total 0–24AUC was calculated by adding the 0–24 AUC from a 25 mg/kg LD (max: 3 gm) to the 0–24AUC(s) for maintenance dose(s) within the first 24 hours. We compared the total 0-24AUC when the first maintenance dose was timed for the next dosing interval (“scheduled”) to that when the maintenance dose was delayed according to our protocol (“delayed”). We tested the proportion of patients who would be exposed to a vancomycin 0-24AUC > 677 mg-hour/L. Results 16/68 patients were diagnosed with SSTI (goal 24 hr AUC: 400 mg-hour/L) and 52/68 with sepsis, bacteremia/endocarditis, or pneumonia (24 hr AUC: 600 mg-hour/L). Median daily maintenance dose was 1750 mg (range: 875–4,000 mg). For patients with a goal AUC of 400, the 0-24AUC was > 677 mg-hour/L in one patient using the “scheduled” process and in none of the patients using the “delayed” protocol. However, for patients with a goal AUC of 600, the 0-24AUC was > 677 mg-hour/L in 22/52 patients via the “scheduled” process vs. 4/52 patients via the “delayed” protocol. Conclusion For patients with severe gram-positive bacterial infections requiring aggressive dosing of vancomycin, delaying the start of maintenance dosing following a large LD is an effective way to ensure attainment of goal therapeutic AUC within the first 24 hr without placing the patient at increased risk for nephrotoxicity. Disclosures All authors: No reported disclosures.

Background Anti-TNF drugs are effective treatments for the management of inflammatory bowel disease (IBD) but treatment failure is common. The aim of this study was to investigate the association between inflammatory biomarkers, serum concentrations of IFX and antiIFX antibody concentration during induction and maintenance treatment and to investigate the association with disease activity and response to treatment in our patients from 2017 to 2019. Methods Retrospective observational study. We enrolled patients receiving IFX from March 2017 until March 2019. Demographic data, disease characteristics, previous medical treatments and surgeries were recorded. Clinical Activity Index (Harvey Index and Parcial Mayo Score) and CRP, faecal calprotectine (FC) and endoscopy or radiological activity were recorded at baseline, and at 6, 12 and 24 months of treatment. IFX serum concentrations and anti-IFX antibody concentration were measured at the end of induction (week 8) and during follow-up (6, 12 and 24 months). Results One hundred and eighty-one IBD patients were treated during the study period, and 175 patients were included: 128 (73.1%) Crohn’s disease (CD), 46 (26.3%) ulcerative colitis (UC) and 1 (0.6%) indeterminated colitis (IC). 95 male, 85 female, mean age 45 years (±15); 93% were naive to IFX. 73.6% started IFX combined with inmunomodulator treatment. At week 0, 80% had an active disease (Global Physician Assessment), 58.8% had CRP >5 μg/dl and 62% had FC > 150 mg/kg. At 12 months, 126 patients continued under IFX, and 68% had an stable disease and 44% were intensified. Thirty-six per cent had CRP > 5 μg/dl and 37% FC>150 mg/kg. At 24 months, 90 patients continued with IFX, from which 80% were stable and 43% were intensified.38% had CRP >5 μg/dl and 26% FC >150 mg/kg. Patients with post-induction (week 8) serum IFX concentration >7 μg/ml had more stable disease (p: 0.04) at that moment and IFX serum concentration > 3 μg/ml at 18 months was corelationated with no inflammation at endoscopy or radiology (p: 0.025). In the multivariate analysis stenosant phenotype and CRP < 5 mg/dl at 6 months were relationated with early stop of IFX treatment ( Conclusion Our study shows that IFX levels >7 μg/ml correlates with a better clinical response. Disease phenotype and inflammatory parameters could influence in long time maintenance treatment. Drug-level monitoring and measurement of baseline inflammatory parameters may improve the management of IBD.

Background Invasive fungal infections (IFI) continue to affect the immunocompromised patient population. Many of these patients require antifungal prophylaxis. Voriconazole is an azole antifungal that has been utilized for preventing IFIs but does not have an approved indication for prophylaxis. Methods Adult patients admitted to Duke University Hospital from January 1, 2005 to December 31, 2015 who had received at least 2 days of systemic voriconazole as primary prophylaxis were included in this retrospective medical records review. Demographics, underlying comorbidities, adverse events, drug interactions, voriconazole blood concentrations, and microbiological data were assessed. Results Our review identified 403 patients receiving voriconazole for primary prophylaxis. 220 (55.6%) were male, 303 (75.2%) were Caucasian, and the mean age was 46.0 ± 15.7 years. 233 (57.8%) had leukemia, and 63 (15.6%) had lymphoma. 301 (74.7%) underwent hematopoietic transplant (BMT), and 45 (11.2%) had a solid-organ transplant. 176 (43.7%) patients received chemotherapy and 261 (64.8%) received immunosuppressive drugs. The mean voriconazole total daily maintenance dose was 416.1 ± 65.9 mg (5.5 ± 1.6 mg/kg/day). Patients received inpatient voriconazole for a mean of 19.5 ± 16.5 days. 371 (92.1%) patients received a concomitant interacting drug. Only 140 (43.7%) patients had therapeutic drug monitoring. The mean first voriconazole serum concentration was 1.8 ± 1.7 mg/L. 87 (21.6%) patients discontinued voriconazole prematurely; 41 (10.2% overall) of these patients had an adverse event requiring discontinuation. 5 had breakthrough fungal infections with microbiological data identifying a fungal species, which included Rhizopus spp. among others. Conclusion Voriconazole is frequently used for primary prophylaxis of IFIs and most commonly in BMT. It appears to be relatively well tolerated with some adverse side-effects (~10%) despite many potential drug–drug interactions and provides appropriate fungal coverage for many immunosuppressed patients. However, few patients had breakthrough fungal infections while receiving voriconazole. In a real-world setting, voriconazole can provide antifungal prevention in certain high-risk patients. Disclosures All authors: No reported disclosures.

Several observational studies have reported an association between higher serum bicarbonate level and high mortality risk in dialysis patients. However, in such studies mere discovery of associations does not allow one to infer causal relationships. This association may be related to inadequate dietary protein intake that may lead to less acid generation and hence a higher serum bicarbonate level. Since undernutrition is a strong predictor of death in hemodialysis patients, the observed association may be an epiphenomenon and not a biologically plausible relationship. Higher protein and fluid intake between two subsequent hemodialysis treatments may lead to lower serum bicarbonate level. This low bicarbonate level may appear protective, as patients with higher food intake and better appetite generally exhibit greater survival. In the contemporary three-stream proportioning system of hemodialysis treatment, the bicarbonate concentrate is separate from the acid concentrate, and the contribution of the acid concentrate organic acid (acetate, citrate or diacetate) to the delivered bicarbonate pool of the patient is negligible. The concept of ‘total buffer’ that assumes that the combination of bicarbonate and acetate concentrations in the dialysate are added equally as bicarbonate equivalents is likely wrong and based on the misleading notion that the acetate of the acid concentrate is fully metabolized to bicarbonate in the dialysate. Given these uncertainties it is prudent to avoid excessively high or low bicarbonate levels in dialysis patients.

Previous work showed a higher prevalence of macrolide/azalide resistance in provinces of Canada where azithromycin was the major treatment for Streptococcus pneumoniae as compared with regions where clarithromycin was the dominant treatment. These data provided a way to test the mutant selection window hypothesis, which predicts that the serum drug concentration (AUC(24)) relative to the mutant prevention concentration (MPC) would be higher for clarithromycin than for azithromycin.The MIC and MPC were determined for 191 penicillin/macrolide-susceptible clinical isolates of S. pneumoniae with azithromycin, clarithromycin and erythromycin using agar plate assays.The MIC(50/90) (mg/L) and MPC(50/90) (mg/L), respectively, were as follows: azithromycin 0.13/0.25 and 1/4; clarithromycin 0.031/0.063 and 0.13/0.5; erythromycin 0.063/0.13 and 0.25/2. We calculated from published pharmacokinetic values that the AUC(24)/MPC(90) for azithromycin was 0.85; for clarithromycin it was 96, and for erythromycin base and estolate it was 4 and 10, respectively. Thus the AUC(24)/MPC(90) was about 50 times higher for clarithromycin than for azithromycin.The elevated prevalence of azithromycin resistance may derive in part from a low value of AUC(24)/MPC(90) and/or time above MPC, since previous work indicates that the number of prescriptions per person was similar in the geographical regions examined.

Background Cefepime is a cephalosporin active against most Gram positive and negative bacteria and is used in the management of bone and joint infections (BJIs). Intravenous (IV) perfusion is the standard route of administration. The Subcutanoeous (SC) route may present an interesting alternative in case of outpatient care or when IV perfusion is not possible. The aim of this study was to demonstrate that the SC route of administation for cefepime provides effective serum concentrations in the treatment of BJIs without route-specific side effects. Methods Descriptive analysis of a bi-center retrospective observational study from January 2011 to February 2017 in patients with an BJI treated with cefepime SC and who had a cefepime plasma level dosage. Cefepim Cmax and Cmin were considered optimal if they were superior to five MIC. Results Eleven patients were included with 21 dosages of cefepime SC, 12 Cmax and nine Cmin. The mean age of the patients was 58 ± 17 years and the mean body mass index was 26.6 ± 5.6. Cefepime was used for the management of infections with at least one Gram-negative bacillus (GNB) (64% of infections were plurimicrobial). Combination with at least one other antibiotic was found in 68% of cases. The median Cmax and Cmin levels were 57 mg/L (39.5–124) and 14 mg/L (0–42), respectively. Cmax was above five MIC for all patient and Cmin was above this threshold in eight (80%) patients but still well above the MIC of GNB. No local complications related to the SC administration of cefepime has been described. Conclusion Plasma concentration during SC administration of cefepime seems to reach similar value to the IV route founded in the literature for BJI management. SC administration appears to be a well-tolerated alternative in the management of BJI. Further prospective clinical efficacy studies are needed. Disclosures All authors: No reported disclosures.

Background Ibalizumab (IBA) is a long-acting humanized monoclonal antibody that binds domain 2 of the CD4 receptor and blocks HIV-1 infection of host cells. TMB-301 was a 24-week, Phase 3 clinical trial conducted in 40 heavily treatment-experienced patients with multidrug-resistant (MDR) HIV-1 investigating the safety, efficacy and tolerability of IBA. Patients received a 2,000 mg IBA loading dose followed by 800 mg every 2 weeks by intravenous infusion plus an optimized background regimen. Viral load 30 μg/mL throughout the dosing period. Both Cpeak and Ctrough (Day 7 and Week 25 IBA concentrations) were decreased with increased body weight. The median Ctrough in the high body weight group (≥85 kg) was 0.23 μg/mL. The mean RO was >85% throughout the dosing period. The 2,000 mg loading dose helped to reach >85% RO after the initial dose and maintain high levels of RO throughout the dosing period. Elevation in RO was generally associated with increased IBA serum concentrations; concentrations ≥0.13 μg/mL supported ≥85% CD4 RO. After IBA administration, down-modulation of surface CD4 receptors by up to 20% was observed. There was no apparent association between IBA serum concentration and RD probably due to high inter-individual variation. Conclusion Dosing regimen of 2,000 mg loading dose followed by 800 mg every 2 weeks was sufficient to support high levels of RO and to maintain the drug concentration above the therapeutic level. Disclosures P. N. Kumar, TheraTechnologies: Consultant and Investigator, Consulting fee and Research grant. ViiV: Consultant, Investigator and Shareholder, Research grant and Speaker honorarium. Merck: Investigator and Shareholder, Research grant. Gilead: Consultant, Investigator and Shareholder, Consulting fee and Research grant. S. Weinheimer, TaiMed Biologics: Employee, Salary. Z. Cohen, Theratechnologies Inc.: Employee, Salary. C. Marsolais, Theratechnologies Inc.: Employee, Salary. K. L. Kuo, TaiMed Biologics Taiwan: Employee, Salary. S. Lewis, TaiMed Biologics: Employee, Salary.

【The purpose of the present study was to evaluate the bioequivalence of two choline alphoscerate soft capsules, Gliatilin soft capsule (Daewoong Pharmaceuticals Co., Ltd.) and Cholicerin soft capsule (Sam Chun Dang Pharm. Co., Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). Serum concentrations of choline after oral administration of choline alphoscerate were determined using a validated LC/MS/MS method. This method showed linear response over the concentration range of 0.5-20 ${\mu}g$ /mL with correlation coefficient of 0.9999. The lower limit of quantitation using 100 ${\mu}L$ of serum was 0.5 ${\mu}g$ /mL which was sensitive enough for pharmacokinetic studies. Thirty six healthy male Korean volunteers received each medicine at the choline alphoscerate dose of 1200 mg in a $2{\times}2$ crossover study. There was a one-week washout period between the doses. Blood samples were taken at predetermined time intervals up to 8 hr. $AUC_t$ (the area under the serum concentration-time curve from time 0 to 8 hr) was calculated by the linear trapezoidal rule method. $C_{max}$ (the maximum serum drug concentration) and $T_{max}$ (the time to reach $C_{max}$ ) were compiled from the serum concentration-time data. Analysis of variance was carried out using logarithmically transformed $AUC_t$ and $C_{max}$ . No significant sequence effect was found for all of the bioavailability parameters, indicating that the crossover design was properly performed. The 90% confidence intervals of the $AUC_t$ ratio and the $C_{max}$ ratio for Cholicerin/Gliatilin were log0.9998-log1.1172 and log0.9938-1.0944, respectively. These values were within the acceptable bioequivalence intervals of log0.80-log1.25. Thus, the criteria of the KFDA guidelines for the bioequivalence was satisfied, indicating Cholicerin soft capsule and Gliatilin soft capsule are bioequivalent.】

OBJECTIVE To compare the pharmacokinetics of various formulations of levetiracetam after oral administration of a single dose to healthy dogs. ANIMALS 6 neurologically normal mixed-breed dogs. PROCEDURES A crossover study design was used. Blood samples for serum harvest were collected from each dog before and at various points after oral administration of one 500-mg tablet of each of 2 generic extended-release (ER) formulations, 1 brand-name ER formulation, or 1 brand-name immediate-release (IR) formulation of levetiracetam. Serum samples were analyzed to determine pharmacokinetic properties of each formulation by means of ultra–high-performance liquid chromatography with tandem mass spectrometry. RESULTS No dogs had clinically important adverse effects for any formulation of levetiracetam. All ER formulations had a significantly lower maximum serum drug concentration and longer time to achieve that concentration than did the IR formulation. Half-lives and elimination rate constants did not differ significantly among formulations. Values for area under the drug concentration-versus-time curve did not differ significantly between ER formulations and the IR formulation; however, 1 generic ER formulation had a significantly lower area under the curve than did other ER formulations. CONCLUSIONS AND CLINICAL RELEVANCE All ER formulations of levetiracetam had similar pharmacokinetic properties in healthy dogs, with some exceptions. Studies will be needed to evaluate the clinical efficacy of the various formulations; however, findings suggested that twice-daily administration of ER formulations may be efficacious in the treatment of seizures in dogs.

The equivalencies of generic drugs are assessed by biological equivalency tests. These tests are conducted on healthy subjects by the crossover method in comparison with the original product, which makes them a useful method for comparing bioequivalencies among generics. However, since a large variation in the results is sometimes observed, we decided to determine what causes this.We requested 28 companies to provide biological equivalency test results for pravastatin sodium tablet (23 products) and compared pharmacokinetic parameters among them. There was a large variation in pharmacokinetic parameters, especially in maximum serum drug concentration, area under the serum concentration to time curve and elimination half-life, though there were no differences between the original product and generic product in each test.On comparing individual parameters from two tests that were carried out according to nearly the same protocol, there was a marked difference in the distribution of data among subjects, indicating that this was a factor causing parameter differences between tests. Thus, when pharmacists are thinking of using a generic drug, it is important for them to notonly consider average parameter values but also the process by which these values have been obtained.

Single-dose pharmacokinetics of sulfadimethoxine were determined in six adult camels (Camelus dromedarius) following administration of a mean dosage of 17.5 +/- 2.7 mg/kg both i.v. and p.o. Serial blood samples were collected through an indwelling jugular catheter intermittently for 5 days for both routes. Sulfadimethoxine was assayed using high-performance liquid chromatography. Serum drug concentration versus time data for each animal was subjected to linear regression, with the best-fit model selected based on residual analysis. The data fit best into a two-compartment open model, with first-order input for oral administration. For orally administered drug, mean maximum serum concentration of 19.3 +/- 1.7 microg/ml was reached at 11.41 +/- 2.59 hr, with an elimination rate constant of 0.09/hr +/- 0.05/hr and an elimination half-life of 11.7 +/- 3 hr. Mean peak serum concentration following i.v. administration was 223 +/- 48 microg/ml. Mean volume of distribution at steady state was 0.393 +/- 0.049 L/kg. Elimination rate constants differed with i.v. and oral administration, suggesting a flip-flop model. Oral bioavailability was 103% +/- 38%. Comparison of maximum serum concentrations to the microbial breakpoint concentration reported for sulfadimethoxine (512 microg/ml) suggests that the dose used in this study, 17.5 +/- 2.7 mg/kg, is insufficient for achieving therapeutic serum levels.

Objective:To summarize the results of serum drug concentration monitoring in the Tenth People's Hospital affiliated to Tongji University from 2003 to 2009.Methods:Serum concentrations of sodium valproate(255 cases),phenytoin sodium(33 cases),carbamazepine(48 cases) and digoxin(141 cases) were determined by immune fluorescence polarization method and the results were statistically analyzed.Results:Sodium valproate was the most frequently monitored drug among the three antiepileptic drugs,which accounted for 75.89%,while phenytoin sodium was the least.Serum concentration of carbamazepine of thirty-five cases was within the normal range,accounting for 72.92%(35/48),which was the highest among the three antiepileptic drugs.Serum concentration of digoxin of 114 cases was within the normal range,accounting for 80.85%(114/141).Conclusion:Serum drug concentration monitoring plays an important role in clinic.Its significance should be interpreted in conjunction with clinical manifestation.

Objective—To determine effects of tricyclic antidepressants (TCA) on the ECG of dogs treated for behavioral conditions and to examine correlations between ECG findings and serum concentrations of these medications. Design—Repeated-measures study. Animals—39 client-owned dogs with behavioral problems. Procedure—Two groups of dogs with behavioral problems were evaluated. In group 1 (n = 20), ECG tracings were recorded before starting treatment with TCA and again after treatment for ≥ 1 month. Dogs in group 2 were already on long-term maintenance amounts of antianxiety medication when ECG tracings were recorded and serum concentrations of medications were obtained. Results—Significant differences were not detected for dogs in group 1 between ECG values measured before and after TCA administration. The ECG values for dogs in group 2 did not differ significantly from the mean of group-1 dogs before receiving medication or from the reference range used at our facility. Duration of the P wave had a significant positive correlation with serum concentrations of clomipramine but significant negative correlation with serum concentrations of amitriptyline. The QT interval corrected for heart rate had a significant negative correlation with serum concentrations of amitriptyline. Conclusion and Clinical Relevance—Amitriptyline and clomipramine administered at standard dosages apparently do not cause ECG abnormalities in healthy dogs with behavioral problems. These medications should be used cautiously in dogs with conduction abnormalities, and clinicians should periodically monitor ECG and use good clinical judgment to weigh risks and benefits of medications for the safety of each dog. (J Am Vet Med Assoc 2000;216: 1571–1575)

Pharmacokinetic studies on the trypanocidal drug homidium bromide using a competitive enzyme immunoassay (detection limit 0.1 ng/mL) are reported for non-infected Friesian and Boran steers following treatment with homidium bromide at a dose of 1.0 mg/kg b.w. Following intravenous (i.v.) treatment of Friesian steers (n = 5), the mean serum drug concentrations were 31.9 +/- 2.1 and 3.9 +/- 0.4 ng/mL at 1 and 24 h, respectively. The decline in serum drug concentration was tri-exponential with half-lives of 0.064 +/- 0.037 h for t1/2 alpha, 7.17 +/- 1.87 h for t1/2 beta and 106.3 +/- 6.6 h for t1/2 gamma for distribution and elimination phases 1 and 2, respectively. Drug was detectable in serum for 17 days following treatment. The mean residence time (MRT) was 63.4 +/- 7.5 h. Following intramuscular (i.m.) treatment of Friesian steers (n = 5), the drug concentration at 1 h after treatment was 72.5 +/- 2.2 ng/mL. This declined to 9.8 +/- 1.8 ng/mL at 24 h. Low concentrations of between 0.1 and 0.3 ng/mL remained in circulation for up to 90 days post-treatment. Following intramuscular treatment of Boran steers (n = 5), the mean serum drug concentration at 1 h after treatment was 112.1 +/- 40.3 ng/mL. By 24 h after treatment, the concentration had fallen to 13.0 +/- 3.3 ng/mL. Thereafter, the serum drug concentration-versus-time profile and the pharmacokinetic parameters obtained following non-compartmental analysis were similar to those obtained following intramuscular treatment of Friesian steers.

The Total Testing Process (TTP) refers to the sequence of 11 steps of laboratory testing, beginning with a clinical question prompted by the patient–clinician encounter and concluding with the impact of the test result on patient care. TTP when applied to therapeutic drug monitoring (TDM) emphasizes that TDM must be considered a process involving a series of steps and interrelated activities and not viewed simply as a numerical value for a serum drug concentration. TTP is also an ideal format for organizing and identifying the system-related and patient-centered variables used in outcomes assessment of TDM, as well as providing a template for collecting the cost data needed for economic analyses. Examples are provided for improving application of TDM by practitioners, clinical laboratories, and educators.

Bayesian forecasting offers several important advantages for dosage individualisation in children, although, unlike for adults, its use in this population is much lower. Indeed, currently Bayesian methods are underused in this patient population. The paucity of paediatric population pharmacokinetic parameters, and the unavailability of specific clinical pharmacokinetic software for the whole paediatric population, are the main limitations to the application of Bayesian methods in these patients. When these problems have been overcome, this approach will allow clinicians to achieve therapeutic concentrations more readily, faster and more precisely, thus making the methodology highly attractive in the paediatric setting.

Background Data on ER and IV POS among organ transplant recipients (OTRs) are limited, and the role of TDM is unclear. Methods Retrospective study of patients (pt) receiving any formulation of POS who had serum troughs checked. Therapeutic was defined as 3 1 mcg/mL. Results We analyzed 88 pt and 340 levels (SUS: 88, ER: 197, IV: 55). Eighty-five pt were OTRs (97%), 73 were lung transplant recipients (LT) (83%), 17 had cystic fibrosis (CF) (19%). POS was used for treatment (70%) (probable aspergillosis (38%), possible aspergillosis (10%), mucormycosis (16%), other mycoses (6%)), prophylaxis (19%), and pre-emptive therapy (14%). POS was given for intolerance of or contraindication to other azoles (47%), salvage therapy (10%), resistance (19%), and failure to achieve therapeutic levels with other azoles (6%). Serum concentration/dose ratios were lower with SUS vs. ER/IV (P < 0.0001) but were similar in ER/IV groups (P = 0.51) (Figure). There was no difference in serum levels between pt receiving ER vs. IV POS at 300 mg once daily (median 1.2 vs. 1.3 mcg/mL, therapeutic 70% vs. 73%, P = 0.57 and >0.99, respectively). 3 pt had levels £ 0.2 mcg/mL on 300 mg ER: 2 had CF and had undergone LT (0.2 and 0 mcg/mL) and 1 had short-gut syndrome (0.1 mcg/mL). Sixty-six percent and 67 % of pt receiving ER or IV POS (300 mg once daily) achieved initial therapeutic levels, respectively; of these, 87% and 83% had median therapeutic follow-up levels, respectively. Serial levels were available for 7 pt whose dose was increased from 300 to 400 mg ER once daily for subtherapeutic levels. 4/7 pt achieved therapeutic levels on 400 vs. 0/7 on 300 mg ER once daily (P = 0.069). Metoclopramide use and CF were associated with subtherapeutic vs. therapeutic levels (25% vs. 4% and 37% vs. 13%, respectively, P = < 0.05). When pt with CF were excluded, neither age nor body mass index were associated with POS levels. CF pt had lower levels than non-CF pt on a dose of 300 mg ER once daily (median 0.8 vs. 1.3 mcg/mL, P = 0.018). Conclusion Therapeutic levels are more reliably achieved with ER & IV POS compared with SUS POS. Serial TDM is unnecessary for most, but is recommended for pt with CF or those on metoclopramide. Dose increases may effectively increase levels. Novel dosing strategies are needed for CF. Disclosures R. K. Shields, Astellas: Received research funding, Research support. Merck: Received research funding, Research support. C. J. Clancy, Merck: Received research funding, Research support. Astellas: Received research funding, Research support. Cidara: Received research funding, Research support. Astellas: Scientific Advisor, Advisory board. Merck: Scientific Advisor, Advisory board. Cidara: Scientific Advisor, Advisory board. Medicines Company: Scientific Advisor, Advisory board.

TDM has greatly contributed to explaining and minimising the toxicity of agents such as theophylline, phenytoin, aminoglycosides and digoxin. The significant use of drugs with narrow therapeutic ranges will continue to require TDM resources to be available and convenient. Improved methods of characterising drug toxicities using pharmacokinetic parameters will extend the use of TDM to effectively optimise the dosage regimens of additional toxic therapies such as antineoplastics and certain investigational agents.

Fifteen Boran cattle from a trypanosomiasis-free area were injected intramuscularly with isometamidium chloride at a dose of 1 mg/kg body weight. Thereafter, the cattle were challenged at monthly intervals with Glossina morsitans centralis infected with one of three populations of Trypanosoma congolense (IL 3893, IL 3889 or IL 1180) until all animals became infected. Isometamidium concentrations in the sera of these cattle were measured using a competitive enzyme-linked immunosorbent assay over the first 105 days following treatment. All cattle challenged with IL 3893 or IL 3889 developed infection following the first challenge, at which time the mean serum drug concentration in all treated cattle was 6 ng/ml. Cattle challenged with IL 1180 became infected following 6 to 8 monthly challenges. The mean serum drug concentration in these cattle at the time of their third monthly challenge with IL 1180 was 0.75 ng/ml. Trypanosome populations IL 3893 and IL 3889 were considered to be highly resistant to isometamidium, while IL 1180, relatively sensitive. It was therefore concluded that T. congolense persisting at serum isometamidium concentrations greater than 0.75 ng/ml can be considered moderately resistant, while those persisting at concentrations greater than 6 ng/ml can be considered markedly resistant. These results will be most valuable in the investigation of isometamidium resistance of T. congolense in the field.

The use of Bayesian and threshold probabilities is examined with respect to the range of probabilities of toxicity for which obtaining a patient's serum drug concentration leads to information that is potentially useful in altering a clinical decision. For the situation of potential drug-induced toxicity, three threshold probabilities are needed to characterize the decision process: the decision threshold for deciding between continuing and discontinuing the drug regimen, the testing threshold that separates the decision to continue the regimen without testing the serum drug concentration from the decision to test before deciding, and the companion testing threshold that separates the decision to discontinue the regimen without testing from the decision to test before deciding. For digoxin, theophylline, aminoglycosides, vancomycin, and phenytoin, three prototypical decision threshold probabilities, 0.33, 0.2, and 0.1, are used, along with published true-positive and false-positive rates, to calculate serum concentration testing thresholds for each drug. Practitioners can be more effective in their use of serum drug concentration data when a Bayesian approach to probability assessment is used in conjunction with testing thresholds.

It is apparent that the use of digitalis preparations, particularly digoxin, is important in patients with systolic left ventricular dysfunction, cardiomegaly, and congestive heart failure. Several historic studies suggest benefit, but more recently completed, well-designed, clinical trials have convincingly demonstrated that worsening congestive heart failure can be prevented and exercise capacity increased with digoxin. The precise dose and subsequent serum drug concentration giving the best safety-efficacy profile have not yet been determined. Importantly, the effect of digoxin on mortality is unknown. However, from a theoretic standpoint, this drug may fare well in ongoing mortality-end point clinical trials. The answer to the question, "Do digitalis glycosides still have a role in congestive heart failure?" is, therefore, absolutely!

In order to investigate the utility of therapeutic monitoring of mexiletine aided by the saliva drug levels, serum (total and unbound fraction) and saliva drug concentrations were measured in six inpatients with ventricular arrhythmia who were given an oral daily dose of 150 or 300 mg (t. i. d.) of mexiletine hydrochloride.Mexiletine levels in saliva were consistently much higher than the levels in serum of the patients. Saliva level to total and unbound serum drug concentration ratio (S/S ratio) varied markedly among patients from 4.5 to 32.0 and from 9.6 to 68.6, respectively, on the first day of medication. The predicted levels of mexiletine in the serum on day 7 and day 14 using the mean S/S ratio obtained on the first day of medication were almost identical to the observed levels in three of these patients, who showed a small ratio of saliva to total serum concentration, less than about 9 (or 21 for the ratio to unbound concentration). There was no correlation between the mexiletine level in saliva and the salivary flow rate.Four patients who received the drug at a daily dose of 300mg showed almost favorable trough drug levels in the serum total fraction ranging from 0.164 to 0.583 μg/ml, and ventricular premature contraction (VPC) in these patients was almost completely reduced (94.7-100.0%), except for one non-responder. Two patients who received 150 mg of the drug showed steady-state trough levels in the serum total fraction of less than 0.1μg/ml and the VPC of one of these two patients was hardly controlled. We, therefore, increased the daily dose to 300 mg in this patient, who was well controlled thereafter.From these findings, it is suggested that it may be possible to estimate the serum mexiletine levels from the saliva drug levels by using the initial S/S ratios inpatients with ratios of less than about 9.

In order to evaluate the results of slow-release of metronidazole colon-targeted capsules，this study was undertaken to examine the pharmacokinetics of metronidazole colon-targeted capsules, normal reference tablets and colon delivery capsules in dogs. The level of metronidazole and its metabolites in serum simultaneously were measured by high performed liquid chromatography (HPLC). According to the serum drug concentration-time curves of metronidazole, pharmacokinetic parameters were calculated. The results indicated that the pharmacokinetic parameters of colon-targeted capsules were comparable to those of colon delivery capsules in dogs. But Tmax of colon-targeted capsules and normal reference tablets have significant difference. Other pharmacokinetic parameters of colon-targeted capsules and normal reference tablets were similar with each other.

When delivering several intravenous drug doses from a single bag, it is generally necessary to throw away any drug that remains in the bag, if the amount is insufficient to deliver the next dose. An algorithm has been developed to allow all of the drug in a bag to be used. Based on standard pharmacokinetic equations, the algorithm calculates the time when the remainder should be given, so that a desired peak serum drug concentration is achieved on the next dose. The algorithm requires as inputs the time limit on the bag, the dosing interval and the size of the dose. This algorithm applies only to drugs that obey single compartment, first-order linear kinetics (e.g. aminoglycosides), but is easily modified for other situations. In conjunction with computer-assisted infusion, use of the algorithm may potentially reduce the cost of aminoglycoside administration by reducing clinical drug waste.

The mutant prevention concentration (MPC) is a new measure of antibiotic potency above which a microbe must attain two concurrent resistance mutations for growth. For some C-8-methoxy fluoroquinolone-pathogen combinations, the value of MPC is below human serum drug concentration achieved with standard doses. Although untested clinically, such a low value of MPC, coupled with high serum concentration, should allow these fluoroquinolones to restrict severely the selection of resistant mutants when used as monotherapy. Compounds that cannot meet the MPC-pharmacokinetic criterion will enrich resistant mutants unless they are a part of combination therapy. Separation of fluoroquinolones into groups suitable for monotherapy or for combination therapy, followed by appropriate adminstration, may help extend the lifespan of the fluoroquinolones.

Extended-release products are designed to prolong the absorption of drugs with short half-lives, thereby allowing longer dosing intervals while minimizing fluctuations in serum drug levels. The relationship between serum drug concentration and clinical effects of antiepileptic drugs (AEDs) can be complex and reducing fluctuations in serum drug levels is not equally advantageous for all AEDs. Extended-release formulations have been shown to be particularly valuable for carbamazepine, whereas for other AEDs advantages, other than prolongation of the dosing interval, have not been clearly demonstrated. Differences in bioavailability may exist between extended-release and immediate-release formulations and among different brands of extended-release products. Therefore, when switching from one formulation to another, careful monitoring of clinical response and attention to the need for dose adjustment are warranted.

The development of an adverse drug reaction (ADR)-monitoring program using standardized screening procedures in a 650-bed hospital is described. A concurrent ADR-reporting system that relied on health-care professionals to report observed ADRs to the pharmacy had generated just two ADR reports during the previous year. The pharmacy developed a program that used standardized procedures to screen for ADRs. The Technicon computer was programmed to screen the previous day's orders for antidotes or "tracer" drugs. In addition, pharmacists screened all laboratory reports of serum drug concentration determinations and positive tests for Clostridium difficile toxin. Spontaneous reporting of ADRs by nurses and physicians was strengthened by use of a revised notification form, newsletters, and inservice-education programs. During the first seven months of the program, 298 ADRs were identified, 15 of which were submitted to FDA. The standardized screening procedures accounted for 149 reports. Pharmacists reviewed an average of 21 reports of high serum drug concentrations each month; on average, 11 of these reports involved ADRs. Screening of microbiology laboratory reports identified 29 ADRs. Physicians reported ADRs infrequently and were likely to report only serious or unexpected reactions. Nurses and pharmacists identified reactions sporadically. Quality assurance auditors were consistent in screening ADRs, but not all reported reactions proved to be ADRs. The use of standardized screening procedures was effective in this pharmacy-based ADR-monitoring program.

The aim of the present study was to assess the precision and bias of a priori methods in the estimation of lithium dosage requirement among bipolar patients. The charts of 82 Diagnostic and Statistical Manual of Mental Disorder-fourth edition bipolar patients with previous history of lithium intoxication were reviewed. After excluding patients who had discontinued lithium treatment, 69 patients were entered to the study. Another 60 bipolar patients without history of lithium intoxication were also included in the study. The demographic data regarding factors thought to affect serum lithium concentrations, including gender, weight, and renal function, was retrospectively collected. Predicted daily lithium doses were calculated by using the new equation derived by the present authors and a priori methods proposed by Pepin et al., Zetin et al., Terao et al. and Keck et al. Mean error was calculated to assess the precision and bias of each a priori method. The Zetin method, the Terao method, and the Keck method had a significant tendency to overpredict dosage requirement. The Pepin method significantly underpredicted dosage. Only the 95% confidence interval of mean error of the present authors' equation was across zero. The present authors' equation represents a precise approach to estimate the lithium dose requirement and is easy to calculate. Regardless of the accuracy of each a priori method in predicting a patient's drug dosage, there is no substitute for proper serum drug concentration monitoring and good clinical judgment. Predictions made by any method should always be assessed clinically before applying its use in a patient.

Objectives Sublethal bactericidal antibiotics promote the formation of multidrug-tolerant persisters. Clinically, serum drug concentration increases gradually and reaches the peak level with high killing efficiency some time after administration. This study aimed to investigate if the initial low antibiotic concentration would promote persister formation in Klebsiella pneumoniae, an increasingly important nosocomial pathogen. Methods Time-dependent killings of K. pneumoniae by different types of bactericidal antibiotics were conducted to determine the existence of multidrug-tolerant K. pneumoniae persisters. Killing experiments with antibiotic gradient feeding were then conducted for a K. pneumoniae laboratory strain (ATCC 10031) and a clinical isolate (YWSCU-03) by adding antibiotics step by step until the drug peak serum concentration was attained. Results Multidrug-tolerant persisters indeed existed in K. pneumoniae and the persistence decreased with increasing drug concentrations or prolonged treatments. Antibiotic gradient feeding, to simulate a gradual increase in serum drug concentration, not only significantly elevated the persistence of ATCC 10031 and YWSCU-03, but also increased the frequency of drug-resistant mutant formation in YWSCU-03. Conclusions After administration, the initial low serum drug concentration could promote the formation of multidrug-tolerant bacterial persisters, which could survive the lethal drug concentrations attained later and potentially render the antibiotic treatment fruitless. Therefore, antibiotic treatments should be based on the comprehensive analysis of, not only drug pharmacokinetics, but also the synergistic effect between pharmacokinetics and persister formation.

In this case report we describe an interaction between clozapine and fluvoxamine in two physically healthy patients meeting the DSM-IIIR criteria for paranoid schizophrenia. The substantial rise of clozapine serum levels suggest that caution should be exercised when combining fluvoxamine with clozapine as the clozapine concentration may increase by a factor of 5-10.

The aim of the present chapter is to discuss therapeutic drug monitoring (TDM) of the established and newer antiepileptic drugs (AEDs), based on their pharmacokinetic properties and mode of action. Analytical methods for the determination of the serum concentrations of these drugs are also briefly described. Due to the nature of epilepsy, it remains problematic to monitor AED treatment by direct observations of clinical response in the individual patient. A reasonably good correlation between serum drug concentration and clinical effect together with large inter-individual differences in the rate of drug clearance, are factors that together with the need to identify toxicity, test compliance and elucidate possible clinical interactions would make TDM desirable. Few studies have been designed primarily to study the serum concentration-effect relationships. As TDM is not widely practiced for the newer AEDs there are no generally accepted target ranges for any of these drugs, and for most a wide range in serum concentration is associated with clinical efficacy. Also, a considerable overlap in drug concentrations related to toxicity and non-response is reported. Further systematic studies designed specifically to evaluate concentration-effect relationships of the new AEDs are urgently needed. Measurements of some of the drugs are undoubtedly of help with individualisation of treatment in selected cases in a particular clinical setting. There are large differences between individuals in response to particular drugs and drug concentrations, thus the primary role of TDM for both the established and newer AEDs is to identify the individual optimum concentration and thus establish a reference value in that patient.

Background PF-06438179, a proposed biosimilar to infliximab, has an identical primary amino acid sequence and similar physicochemical, in vitro, and in vivo functional properties to infliximab. Objectives The Phase I study was designed to demonstrate pharmacokinetics (PK) similarity of PF-06438179 to infliximab sourced from the US (infliximab-US) and EU (infliximab-EU), and between infliximab-EU and infliximab-US. Safety was also evaluated. Methods In this double-blind trial (NCT01844804), 151 healthy volunteers, 18-55 years old were randomized 1:1:1 to one of 3 treatment groups, of which 146 received a single 10 mg/kg IV dose of PF-06438179 (n=49), infliximab-US (n=48), or infliximab-EU (n=49). All subjects provided informed consent. PK was evaluated over a period of 8 weeks and safety and immunogenicity were assessed up to 12 weeks. PK similarity for a given test-to-reference comparison was considered to be demonstrated if the 90% CI of the test-to-reference ratio of the area under curve from time 0 to the last time point (AUC T ), from time 0 to infinity (AUC 0–∞ ), and maximum concentration (C max ) were within the 80.00% – 125.00% bioequivalence (BE) acceptance window. Results The baseline demographics for the 130 subjects evaluable for PK were similar among treatment groups. The 3 study drugs exhibited a similar PK profile, which is characterized by a rapid increase of serum drug concentration during infusion followed by a multi-phasic decline in drug concentrations (Figure). The 90% CI for the ratios of C max , AUC T , and AUC 0–∞ were within the BE acceptance window of 80.00–125.00% for the comparisons of PF-06438179 to infliximab-US or infliximab-EU, and infliximab-EU to infliximab-US. Similar number of subjects experienced AEs among all 3 treatment groups. Overall the frequency and type of AEs reported were similar across all three treatment groups, although the number of AEs was highest in the infliximab-US group. The 3 treatments had a comparable ADA profile with a somewhat lower incidence of ADA response in the PF-06438179 group. No infusion related reactions were reported. Conclusions This study demonstrates PK similarity of PF-06438179 to both infliximab-US and infliximab-EU and of infliximab-EU to infliximab-US. The 3 study drugs were generally safe and well-tolerated in this study. Disclosure of Interest C. Udata Employee of: Pfizer Inc, S. Hua Employee of: Pfizer Inc, D. Yin Employee of: Pfizer Inc, S. Salts Employee of: Pfizer Inc, X. Meng Employee of: Pfizer Inc, M. Rehman Employee of: Pfizer Inc DOI 10.1136/annrheumdis-2014-eular.5377

Population-based pharmacokinetic prediction algorithms have been developed for several medications. A fundamental assumption has been that the kinetics remain constant over time. Carbamazepine (CBZ), however, induces its own metabolism in a concentration- and time-dependent manner. A Bayesian estimation program is presented that models the changing catabolic enzyme activity, linearly related to hepatic microsomal enzyme concentration, along with the serum drug concentration. An Emax model is used for enzyme formation with respect to drug concentration: elimination of enzyme activity is modeled as a first-order process. This program was tested in 22 drug-naive outpatients begun on CBZ monotherapy. The 1 week concentrations were used to prospectively predict concentrations at 1 month of therapy and were very close to actual measurements: prediction bias (mean error of prediction) = -0.1 micrograms/mL and precision (median absolute error of prediction) = 1.2 micrograms/mL. Comparison estimates, made by assuming a constant concentration/dose ratio, had bias = 2.6 micrograms/mL (p0.001) and precision = 2.2 micrograms/mL (p = 0.01). We conclude that (1) CBZ autoinduction is not complete after 1 week of therapy and (2) the methodology permits accurate estimation of CBZ pharmacokinetics.