Outcomes up to age 36 months after congenital Zika virus infection-U.S. states.

BACKGROUND: To characterize neurodevelopmental abnormalities in children up to 36 months of age with congenital Zika virus exposure. METHODS: From the U.S. Zika Pregnancy and Infant Registry, a national surveillance system to monitor pregnancies with laboratory evidence of Zika virus infection, pregnancy outcomes and presence of Zika associated birth defects (ZBD) were reported among infants with available information. Neurologic sequelae and developmental delay were reported among children with ≥1 follow-up exam after 14 days of age or with ≥1 visit with development reported, respectively. RESULTS: Among 2248 infants, 10.1% were born preterm, and 10.5% were small-for-gestational age. Overall, 122 (5.4%) had any ZBD; 91.8% of infants had brain abnormalities or microcephaly, 23.0% had eye abnormalities, and 14.8% had both. Of 1881 children ≥1 follow-up exam reported, neurologic sequelae were more common among children with ZBD (44.6%) vs. without ZBD (1.5%). Of children with ≥1 visit with development reported, 46.8% (51/109) of children with ZBD and 7.4% (129/1739) of children without ZBD had confirmed or possible developmental delay. CONCLUSION: Understanding the prevalence of developmental delays and healthcare needs of children with congenital Zika virus exposure can inform health systems and planning to ensure services are available for affected families. IMPACT: We characterize pregnancy and infant outcomes and describe neurodevelopmental abnormalities up to 36 months of age by presence of Zika associated birth defects (ZBD). Neurologic sequelae and developmental delays were common among children with ZBD. Children with ZBD had increased frequency of neurologic sequelae and developmental delay compared to children without ZBD. Longitudinal follow-up of infants with Zika virus exposure in utero is important to characterize neurodevelopmental delay not apparent in early infancy, but logistically challenging in surveillance models.

Zika-Associated Birth Defects Reported in Pregnancies with Laboratory Evidence of Confirmed or Possible Zika Virus Infection - U.S. Zika Pregnancy and Infant Registry, December 1, 2015-March 31, 2018.

Zika virus infection during pregnancy can cause serious birth defects of the brain and eyes, including intracranial calcifications, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities (1,2). The frequency of these Zika-associated brain and eye defects, based on data from the U.S. Zika Pregnancy and Infant Registry (USZPIR), has been previously reported in aggregate (3,4). This report describes the frequency of individual Zika-associated brain and eye defects among infants from pregnancies with laboratory evidence of confirmed or possible Zika virus infection. Among 6,799 live-born infants in USZPIR born during December 1, 2015-March 31, 2018, 4.6% had any Zika-associated birth defect; in a subgroup of pregnancies with a positive nucleic acid amplification test (NAAT) for Zika virus infection, the percentage was 6.1% of live-born infants. The brain and eye defects most frequently reported included microcephaly, corpus callosum abnormalities, intracranial calcification, abnormal cortical gyral patterns, ventriculomegaly, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities. Among infants with any Zika-associated birth defect, one third had more than one defect reported. Certain brain and eye defects in an infant might prompt suspicion of prenatal Zika virus infection. These findings can help target surveillance efforts to the most common brain and eye defects associated with Zika virus infection during pregnancy should a Zika virus outbreak reemerge, and might provide a signal to the reemergence of Zika virus, particularly in geographic regions without ongoing comprehensive Zika virus surveillance.

Effect of Fremanezumab Monthly and Quarterly Doses on Efficacy Responses.

OBJECTIVE: Exposure-response (E-R) models were developed to provide a description of the time-course of treatment effect for monthly and quarterly dosing regimens of fremanezumab. BACKGROUND: Fremanezumab is a monoclonal antibody for preventive treatment of episodic migraine (EM) and chronic migraine (CM). In phase 2b and 3 clinical studies of fremanezumab, significant reductions in migraine and headache days and other clinical endpoints were observed for patients with EM and patients with CM. Development of E-R models relating individual-specific measures of drug exposure to clinical endpoints provides a more granular understanding of the expected effects of different doses on therapeutic outcomes by accounting for variability in pharmacokinetic (PK) properties. METHODS: Data from 2 phase 2b and 2 phase 3 studies of adults with EM or CM were used. Individual exposures were calculated from a population PK model and related to monthly migraine days in EM and moderate-severe (M/S) headache days in CM. Model-based stochastic simulations were performed to compare predicted responses for the various treatment regimens. RESULTS: The effect of average fremanezumab concentration compared to placebo on the reduction in migraine days and M/S headache days was predicted by the models to be similar for 225 mg monthly and 675 mg once quarterly over time for both EM and CM patients. Both regimens were associated with better response than placebo. A similar percent of EM and CM responders was predicted across the range of observed body weights. CONCLUSIONS: Exposure-response evaluations showed that both monthly (225 mg) and quarterly (675 mg) fremanezumab dosing regimens were appropriate in achieving clinical benefit in adult patients with EM or CM.

Population pharmacokinetic modelling and simulation of fremanezumab in healthy subjects and patients with migraine.

AIMS: Fremanezumab is a fully humanized IgG2 Δa/κ monoclonal antibody specific for calcitonin gene-related peptide developed and approved for the preventive treatment of migraine in adults. The population pharmacokinetics (PK) of fremanezumab were characterized in healthy subjects and patients with chronic migraine and episodic migraine, including the effects of intrinsic and extrinsic factors on PK variability. METHODS: Nonlinear mixed effects modelling was performed using NONMEM with data from 7 phase 1-3 clinical trials evaluating selected intravenous and subcutaneous dose regimens. The influence of covariates on fremanezumab PK was assessed and model evaluation was performed through visual predictive checks. RESULTS: A 2-compartment model with first-order absorption and elimination described the PK data well. Typical values for fremanezumab central clearance (0.0902 L/d) and central distribution volume (1.88 L) for a 71-kg subject were consistent with previously reported values for IgG antibodies. Higher body weight was associated with increased central clearance and distribution volume. Effects of other covariates (age, albumin, renal function, sex, race, injection site, and acute, analgesic and preventive medication use for migraine) were not found to statistically significantly influence fremanezumab PK. There was no indication of reduced exposure in participants with positive anti-drug antibody status or with mild to moderate hepatic impairment. Absolute bioavailability was estimated at 0.658. CONCLUSIONS: A comprehensive population PK model was developed for fremanezumab following intravenous and subcutaneous administration in healthy subjects and patients with chronic migraine or episodic migraine, which will be used to further evaluate exposure-response relationships for efficacy and safety endpoints.

Modeling and simulations to support dose selection for eslicarbazepine acetate therapy in pediatric patients with partial-onset seizures.

Modeling and simulations were used to support body weight-based dose selection for eslicarbazepine acetate (ESL) in pediatric subjects aged 4-17 years with partial-onset seizures. A one-compartment pediatric population pharmacokinetic model with formulation-specific first-order absorption, first-order elimination, and weight-based allometric scaling of clearance and distribution volume was developed with PK data from subjects 2-18 years of age treated with ESL 5-30 mg/kg/day. Covariate analysis was performed to quantify the effects of key demographic and clinical covariates (including body weight and concomitant use of carbamazepine, levetiracetam, and phenobarbital-like antiepileptic drugs [AEDs]) on variability in PK parameters. Model evaluation performed using a simulation-based visual predictive check and a non-parametric bootstrap procedure indicated no substantial bias in the overall model and in the accuracy of estimates. The model estimated that concomitant use of carbamazepine or phenobarbital-like AEDs with ESL would decrease the exposure of eslicarbazepine, and that concomitant use of levetiracetam with ESL would increase the exposure of eslicarbazepine, although the small effect of levetiracetam may not represent a true difference. Model-based simulations were subsequently performed to apply target exposure matching of selected ESL doses for pediatric subjects (aged 4-17 years) to attain eslicarbazepine exposures associated with effective and well-tolerated ESL doses in adults. Overall, model-based exposure matching allowed for extrapolation of efficacy to support pediatric dose selection as part of the submission to obtain FDA approval for ESL (adjunctive therapy and monotherapy) in subjects aged 4-17 years, without requiring an additional clinical study.

Race and neonatal respiratory morbidity in the late preterm period.

BACKGROUND: Prematurity is one of the leading causes of perinatal morbidity and mortality. Some studies suggest that respiratory disease may differ by race in early preterm infants. However, the role of race in late preterm neonatal morbidity is not yet established. OBJECTIVE: The objective of our study was to determine whether neonatal respiratory morbidity differs by race in neonates born late preterm. STUDY DESIGN: This was a secondary analysis of a randomized trial of women at high risk for late preterm delivery (Antenatal Late Preterm Steroids). Our study was limited to women with nonanomalous, singleton gestations, delivering between 34+0 to 36+6 weeks. Women were categorized into 4 groups by race: Black, White, Asian, or other/mixed. The primary outcome was a neonatal composite of treatment in the first 72 hours (continuous positive airway pressure or high-flow nasal cannula >2 hours, oxygen >4 hours, extracorporeal membrane oxygenation or mechanical ventilation) or stillbirth or neonatal death before 72 hours. The secondary outcomes included severe respiratory morbidity (the primary outcome extending continuous positive airway pressure or high-flow nasal cannula to >12 continuous hours and oxygen to at least 24 continuous hours), respiratory distress syndrome, transient tachypnea of the newborn, apnea, neonatal intensive care unit admission, bronchopulmonary dysplasia, and surfactant administration. The primary and secondary outcomes were assessed in the active (steroid) and placebo groups separately. We fit a logistic regression model to adjust for confounders related to respiratory morbidity. RESULTS: Of a total of 2331 included women, 26.9% (n=627) were Black/African American, 57.1% (n=1333) White, 3.56% (n=83) Asian, and 12.36% (n=288) were other/mixed. In the placebo group, the rate of the primary outcome was significantly higher in Whites (18.6%) and Asians (22.8%) compared with the African American/Black group (12.3%) (P=.03). Adjusting for confounders, the primary outcome was not significant between the groups. The primary predictor for respiratory morbidity was a prior pregnancy with neonatal respiratory morbidity. Findings were similar in the steroid group, but severe respiratory morbidity was less common in Black infants compared with White infants (adjusted odds ratio, 0.45; 95% confidence interval, 0.24-0.83). However, a prior pregnancy with neonatal respiratory complications was no longer associated with respiratory morbidity after receipt of betamethasone. CONCLUSION: Late preterm respiratory morbidity was similar between racial groups. Although a history of pregnancy with previous neonatal respiratory disease is the strongest risk factor for recurrence, this risk factor is mitigated by the receipt of steroids.

Relationship of the Calcitonin Gene-Related Peptide Monoclonal Antibody Galcanezumab Pharmacokinetics and Capsaicin-Induced Dermal Blood Flow in Healthy Subjects.

Galcanezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide, was recently approved for migraine prophylaxis. The pharmacokinetic/pharmacodynamic (PK/PD) relationship between galcanezumab concentration and inhibition of capsaicin-induced dermal blood flow (CIDBF) was evaluated using first-in-human data following 6 single subcutaneous doses (1 to 600 mg) or multiple (4) 150-mg doses every 2 weeks in 7 cohorts (7 actively treated subjects and 2 placebo-treated healthy subjects). Galcanezumab pharmacokinetics were best described by a 1-compartment model with delayed first-order absorption/linear elimination. Apparent estimates (between-subject variability) of clearance, volume of distribution, absorption rate constant, and lag time were 0.0106 L/h (27%CV), 11.2 L (21%CV), 0.0192 h-1 (89%CV), and 0.202 hours, respectively. Estimated elimination half-life was about 30 days. An effect compartment link model described the concentration-effect relationship; estimated maximum inhibitory effect was 70.5%, and 50% maximum inhibitory effect concentration (IC50 ) was 1060 ng/mL. Galcanezumab showed dose- and concentration-dependent potent and durable inhibition of CIDBF. Simulated effect compartment concentrations were maintained above IC50 after 12 weeks of dosing. Near-maximal CIDBF inhibition occurred with 150 mg biweekly for 12 weeks lasting ≥24 weeks or with ≥30 mg every 2 weeks or 195 mg every 13 weeks. Quantitative modeling of galcanezumab PK/PD supported dose selection for the phase 2 proof-of-concept study.

Concentration-QTc analysis of quizartinib in patients with relapsed/refractory acute myeloid leukemia.

PURPOSE: This analysis evaluated the relationship between concentrations of quizartinib and its active metabolite AC886 and QT interval corrected using Fridericia's formula (QTcF) in patients with relapsed/refractory acute myeloid leukemia (AML) treated in the phase 3 QuANTUM-R study (NCT02039726). METHODS: The analysis dataset included 226 patients with AML. Quizartinib dihydrochloride was administered as daily doses of 20, 30, and 60 mg. Nonlinear mixed-effects modeling was performed using observed quizartinib and AC886 concentrations and time-matched mean electrocardiogram measurements. RESULTS: Observed QTcF increased with quizartinib and AC886 concentrations; the relationship was best described by a nonlinear maximum effect (Emax) model. The predicted mean increase in QTcF at the maximum concentration of quizartinib and AC886 associated with 60 mg/day was 21.1 ms (90% CI, 18.3-23.6 ms). Age, body weight, sex, race, baseline QTcF, QT-prolonging drug use, hypomagnesemia, and hypocalcemia were not significant predictors of QTcF. Hypokalemia (serum potassium < 3.5 mmol/L) was a statistically significant covariate affecting baseline QTcF, but no differences in ∆QTcF (change in QTcF from baseline) were predicted between patients with versus without hypokalemia at the same quizartinib concentration. The use of concomitant QT-prolonging drugs did not increase QTcF further. CONCLUSION: QTcF increase was dependent on quizartinib and AC886 concentrations, but patient factors, including sex and age, did not affect the concentration-QTcF relationship. Because concomitant strong cytochrome P450 3A (CYP3A) inhibitor use significantly increases quizartinib concentration, these results support the clinical recommendation of quizartinib dose reduction in patients concurrently receiving a strong CYP3A inhibitor. CLINICAL TRIAL REGISTRATION: NCT02039726 (registered January 20, 2014).

Population Pharmacokinetic Analysis of BMS-986166, a Novel Selective Sphingosine-1-Phosphate-1 Receptor Modulator, and Exposure-Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants.

Sphingosine-1-phosphate (S1P) binding to the S1P-1 receptor (S1P1R) controls the egress of lymphocytes from lymphoid organs and targets modulation of immune responses in autoimmune diseases. Pharmacologic modulation of S1P receptors has been linked to heart rate reduction. BMS-986166, a prodrug of the active phosphorylated metabolite BMS-986166-P, presents an improved cardiac safety profile in preclinical studies compared to other S1P1R modulators. The pharmacokinetics, safety, and pharmacodynamics of BMS-986166 versus placebo after single (0.75-5.0 mg) and repeated (0.25-1.5 mg/day) oral administration were assessed in healthy participants after a 1-day lead-in placebo period. A population model was developed to jointly describe BMS-986166 and BMS-986166-P pharmacokinetics and predict individual exposures. Inhibitory sigmoid models described the relationships between average daily BMS-986166-P concentrations and nadir of time-matched (day -1) placebo-corrected heart rate on day 1 (nDDHR, where DD represents ∆∆) and nadir of absolute lymphocyte count (nALC). Predicted decreases in nDDHR and nALC were 9 bpm and 20% following placebo, with maximum decreases of 10 bpm in nDDHR due to drug effect, and approximately 80% in nALC due to drug and placebo. A 0.5-mg/day dose regimen achieves the target 65% reduction in nALC associated with a 2-bpm decrease in nDDHR over placebo.

Outcomes of Neonates Born to Mothers With Severe Acute Respiratory Syndrome Coronavirus 2 Infection at a Large Medical Center in New York City.

Importance: Limited data on vertical and perinatal transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and health outcomes of neonates born to mothers with symptomatic or asymptomatic coronavirus disease 2019 (COVID-19) are available. Studies are needed to inform evidence-based infection prevention and control (IP&C) policies. Objective: To describe the outcomes of neonates born to mothers with perinatal SARS-CoV-2 infection and the IP&C practices associated with these outcomes. Design, Setting, and Participants: This retrospective cohort analysis reviewed the medical records for maternal and newborn data for all 101 neonates born to 100 mothers positive for or with suspected SARS-CoV-2 infection from March 13 to April 24, 2020. Testing for SARS-CoV-2 was performed using Cobas (Roche Diagnostics) or Xpert Xpress (Cepheid) assays. Newborns were admitted to well-baby nurseries (WBNs) (82 infants) and neonatal intensive care units (NICUs) (19 infants) in 2 affiliate hospitals at a large academic medical center in New York, New York. Newborns from the WBNs roomed-in with their mothers, who were required to wear masks. Direct breastfeeding after appropriate hygiene was encouraged. Exposures: Perinatal exposure to maternal asymptomatic/mild vs severe/critical COVID-19. Main Outcomes and Measures: The primary outcome was newborn SARS-CoV-2 testing results. Maternal COVID-19 status was classified as asymptomatic/mildly symptomatic vs severe/critical. Newborn characteristics and clinical courses were compared across maternal COVID-19 severity. Results: In total, 141 tests were obtained from 101 newborns (54 girls [53.5%]) on 0 to 25 days of life (DOL-0 to DOL-25) (median, DOL-1; interquartile range [IQR], DOL-1 to DOL-3). Two newborns had indeterminate test results, indicative of low viral load (2.0%; 95% CI, 0.2%-7.0%); 1 newborn never underwent retesting but remained well on follow-up, and the other had negative results on retesting. Maternal severe/critical COVID-19 was associated with newborns born approximately 1 week earlier (median gestational age, 37.9 [IQR, 37.1-38.4] vs 39.1 [IQR, 38.3-40.2] weeks; P = .02) and at increased risk of requiring phototherapy (3 of 10 [30.0%] vs 6 of 91 [7.0%]; P = .04) compared with newborns of mothers with asymptomatic/mild COVID-19. Fifty-five newborns were followed up in a new COVID-19 Newborn Follow-up Clinic at DOL-3 to DOL-10 and remained well. Twenty of these newborns plus 3 newborns followed up elsewhere had 32 nonroutine encounters documented at DOL-3 to DOL-25, and none had evidence of SARS-CoV-2 infection, including 6 with negative retesting results. Conclusions and Relevance: No clinical evidence of vertical transmission was identified in 101 newborns of mothers positive for or with suspected SARS-CoV-2 infection, despite most newborns rooming-in and direct breastfeeding practices.

Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Modeling of Weight-Based Intravenous Reslizumab Dosing.

Reslizumab 3.0 mg/kg has demonstrated efficacy in clinical studies of patients with eosinophilic asthma and a history of exacerbations. A population pharmacokinetic (PK) model was developed to determine whether 3.0 mg/kg weight-based dosing is appropriate to obtain consistent reslizumab exposures in all patients. PK data in healthy volunteers and patients ≥12 years with moderate to severe asthma, eosinophilic asthma, or nasal polyposis were analyzed from 4 phase 1, 2 phase 2, and 2 phase 3 studies of intravenous (IV) reslizumab (N = 804). Covariates evaluated included age, race, sex, baseline weight, renal and liver function, concomitant medications, and antidrug antibody status. Exposure-response models were developed to characterize key efficacy (blood eosinophil levels, forced expiratory volume in 1 second [FEV1 ], Asthma Control Questionnaire [ACQ-7] scores), and safety end points (muscle disorder adverse events [AEs]). Vial-based dosing was evaluated as an alternative to weight-based dosing. IV reslizumab PK was accurately described by a 2-compartment PK model with 0-order input and first-order elimination. Body weight was the only covariate that significantly influenced PK parameters. However, with weight-based dosing, comparable steady-state exposures were observed across high and low body weights. Greater eosinophil lowering and longer response duration were observed with increasing dose; exposure-related effects on FEV1 and ACQ-7 were also seen, demonstrating the clinical importance of a dosing regimen to optimize reslizumab exposure. The probability of a muscle disorder AE appeared to increase with increasing exposure. Steady-state exposure measures were similar for both dosing regimens, showing vial-based dosing as an alternative method of achieving the benefits of weight-based dosing.

Population Pharmacokinetic Analysis of Quizartinib in Healthy Volunteers and Patients With Relapsed/Refractory Acute Myeloid Leukemia.

Quizartinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor that has shown robust clinical activity in patients with FLT3-internal tandem duplication-mutated relapsed/refractory acute myeloid leukemia (AML). This analysis evaluated the population pharmacokinetics (PK) of quizartinib and its active metabolite, AC886, in a pooled analysis of data from 649 healthy volunteers or patients with AML from 8 clinical trials including the phase 3 QuANTUM-R study. Quizartinib was given as a single dose or multiple once-daily doses of 20, 30, 60, or 90 mg. Nonlinear mixed-effects modeling was performed using observed concentrations of quizartinib and AC886. Strong CYP3A inhibitor use resulted in an 82% increase in the area under the curve (AUC) and a 72% increase in the maximum concentration (Cmax ) of quizartinib. Albumin level, age, and body surface area were statistically significant covariates on quizartinib PK. However, their individual effects on quizartinib AUC and Cmax were <20%. For AC886, strong CYP3A inhibitor use, body surface area and black/African American race were significant covariates. Except for strong CYP3A inhibitor use, the effects on the overall exposure (AUC of quizartinib + AC886) were <20%. The population PK model provided an adequate description of the observed concentrations of quizartinib and AC886 in both healthy volunteers and patients with AML. Only concomitant use of strong CYP3A inhibitors had a clinically meaningful effect on quizartinib PK exposure.

Kerfuffle!

To become disheveled. A kerfuffle is the polite term for a cascading series of errors that can be initiated by a seemingly innocuous event that then leads to other errors that gain in severity and impact. This article describes some of the common kerfuffles that arise in modeling and simulation efforts. The process of eradicating or minimizing the impact of these pharmacometric kerfuffles begins with the recognition that the errors that contribute to the kerfuffle can and should be addressed systematically. They are not just an unpleasant aspect of the job that pharmacometricians must learn to live with in the conscientious execution of their work.

Population Pharmacokinetics and Exposure - Safety Analyses of Nivolumab in Patients With Relapsed or Refractory Classical Hodgkin Lymphoma.

Nivolumab, a fully human immunoglobulin G4 monoclonal anti-programmed death-1 antibody, has demonstrated clinical benefits in multiple tumors, including classical Hodgkin lymphoma. The aim of this study was to characterize the pharmacokinetics (PK) of nivolumab in patients with classical Hodgkin lymphoma using a population approach and to assess the exposure-response (E-R) relationship for safety, thereby supporting the dose recommendation in patients with classical Hodgkin lymphoma. Nivolumab PK and the effect of covariates were consistent with that observed in solid tumors, except that baseline clearance of nivolumab was lower in patients with classical Hodgkin lymphoma by 28%. The E-R analysis for safety, characterized by a Cox proportional hazards model, indicated that the resulting increased nivolumab exposure (average concentration after the first dose) was not a significant predictor of the risk of grade ≥3 drug-related adverse events. Given the acceptable safety profile and observed benefit (65% objective response rate) with the nivolumab 3 mg/kg every 2 week dosing regimen for classical Hodgkin lymphoma, together with the flat E-R safety relationship, nivolumab demonstrated a favorable benefit-risk profile across the range of exposures of 3 mg/kg every 2 weeks in patients with classical Hodgkin lymphoma. Additional model-based simulation suggested that a flat dose of 240 mg every 2 weeks was predicted to produce similar exposures to that of 3 mg/kg every 2 weeks. Therefore, nivolumab 240 mg every 2 weeks is the recommended dosing regimen in the classical Hodgkin lymphoma population.

Population Pharmacokinetic Evaluation and Missed-Dose Simulations for Eslicarbazepine Acetate Monotherapy in Patients With Partial-Onset Seizures.

Given the potential consequences of antiepileptic therapy nonadherence, missed-dose scenarios of 12- to 48-hour dose delays (4-hour intervals) for eslicarbazepine acetate monotherapy were evaluated using simulated plasma concentrations of a population pharmacokinetic model (representing 493 subjects). When 1600-mg doses were delayed 12 to <16 or 36 to <44 hours, simulations showed immediate administration of 1600 mg followed by the same dose at the scheduled time maintained plasma concentrations within the target concentration range. With 16- to 24- or 44- to 48-hour delays, administration of 2400 mg at the scheduled time followed by resumption of 1600 mg/day maintained plasma concentrations within the target concentration range. For exploratory purposes, the population pharmacokinetic model was refined to predict (n = 6 subjects) and also to allow for simulation of cerebrospinal fluid concentrations. Based on the plasma concentration simulations conducted herein, potential dosing recommendations were developed that suggest a missed ESL dose should be taken when remembered, and the usual dose regimen resumed. If it is remembered within 4 hours of the next dose, 1.5 times the usual dose should be taken immediately, the scheduled dose for that day should be skipped, and the usual regimen resumed the next day.

Population Pharmacokinetics and Exposure-Response Analyses of Eslicarbazepine Acetate Efficacy and Safety in Monotherapy of Partial-Onset Seizures.

Eslicarbazepine acetate (ESL) is a once-daily oral antiepileptic drug (AED) indicated for partial-onset seizures (POS). ESL pharmacokinetics (PK) and exposure-response analyses were supported by 2 phase 3 conversion to ESL (1200, 1600 mg) monotherapy studies. The PK model development included 10 phase 1-2 studies (ESL 600-1200 mg daily). Seizure diaries were completed daily; subjects exited if seizures worsened. Exposure-response models were developed for time to study exit, probability of seizure freedom, time to first occurrence of dizziness, headache, and nausea; serum sodium levels were explored. A 1-compartment model with first-order absorption/elimination described ESL PK. Clearance and distribution volume were significantly related to body weight and sex. Higher eslicarbazepine minimum concentration (Cmin ) and use of 1 baseline AED were associated with significantly lower risk of study exit, whereas eslicarbazepine Cmin was a significant predictor of seizure freedom during the last 4 weeks of monotherapy. Eslicarbazepine exposure and the time to first occurrence of adverse events were not related. A shallow negative relationship described the relationship between change from baseline in serum sodium level and eslicarbazepine exposure. Eslicarbazepine apparent clearance and distribution volume estimates were similar to those reported for ESL adjunctive therapy. Dose adjustment based on body weight was not required. The time to study exit and probability of seizure freedom during the last 4 weeks of monotherapy were weakly related to eslicarbazepine exposure. Because the first occurrence of adverse events or hyponatremia were also not significantly related to eslicarbazepine exposure, dose adjustment using plasma eslicarbazepine concentrations is not supported.

Decreased Surgical Site Infection Rate in Hysterectomy: Effect of a Gynecology-Specific Bundle.

OBJECTIVE: We implemented a hysterectomy-specific surgical site infection prevention bundle after a higher-than-expected surgical site infection rate was identified at our institution. We evaluate how this bundle affected the surgical site infection rate, length of hospital stay, and 30-day postoperative readmission rate. METHODS: This is a quality improvement study featuring retrospective analysis of a prospectively implemented, multidisciplinary team-designed surgical site infection prevention bundle that consisted of chlorhexidine-impregnated preoperative wipes, standardized aseptic surgical preparation, standardized antibiotic dosing, perioperative normothermia, surgical dressing maintenance, and direct feedback to clinicians when the protocol was breached. RESULTS: There were 2,099 hysterectomies completed during the 33-month study period. There were 61 surgical site infections (4.51%) in the pre-full bundle implementation period and 14 (1.87%) in the post-full bundle implementation period; we found a sustained reduction in the proportion of patients experiencing surgical site infection during the last 8 months of the study period. After adjusting for clinical characteristics, patients who underwent surgery after full implementation were less likely to develop a surgical site infection (adjusted odds ratio [OR] 0.46, P=.01) than those undergoing surgery before full implementation. Multivariable regression analysis showed no statistically significant difference in postoperative days of hospital stay (adjusted mean ratio 0.95, P=.09) or rate of readmission for surgical site infection-specific indication (adjusted OR 2.65, P=.08) between the before and after full-bundle implementation periods. CONCLUSION: The multidisciplinary implementation of a gynecologic perioperative surgical site infection prevention bundle was associated with a significant reduction in surgical site infection rate in patients undergoing hysterectomy.

Population pharmacokinetic meta-analysis of trabectedin (ET-743, Yondelis) in cancer patients.

OBJECTIVE: To characterise the population pharmacokinetics of trabectedin (ET-743, Yondelis(R)) in cancer patients. METHODS: A total of 603 patients (945 cycles) receiving intravenous trabectedin as monotherapy at doses ranging from 0.024 to 1.8 mg/m(2) and given as a 1-, 3- or 24-hour infusion every 21 days; a 1- or 3-hour infusion on days 1, 8 and 15 of a 28-day cycle; or a 1-hour infusion daily for 5 consecutive days every 21 days were included in the analysis. An open four-compartment pharmacokinetic model with linear elimination, linear and nonlinear distribution to the deep and shallow peripheral compartments, respectively, and a catenary compartment off the shallow compartment was developed to best describe the index dataset using NONMEM V software. The effect of selected patient covariates on trabectedin pharmacokinetics was investigated. Model evaluation was performed using goodness-of-fit plots and relative error measurements for the test dataset. Simulations were undertaken to evaluate covariate effects on trabectedin pharmacokinetics. RESULTS: The mean (SD) trabectedin elimination half-life was approximately 180 (61.4) hours. Plasma accumulation was limited when trabectedin was given every 3 weeks. Systemic clearance (31.5 L/h, coefficient of variation 51%) was 19.2% higher in patients receiving concomitant dexamethasone. The typical values of the volume of distribution at steady state for male and female patients were 6070L and 5240L, respectively. Within the range studied, age, body size variables, AST, ALT, alkaline phosphatase, lactate dehydrogenase, total bilirubin, creatinine clearance, albumin, total protein, Eastern Cooperative Oncology Group performance status and presence of liver metastases were not statistically related to trabectedin pharmacokinetic parameters. The pharmacokinetic parameters of trabectedin were consistent across the infusion durations and dose regimens evaluated. CONCLUSIONS: The integration of trabectedin pharmacokinetic data demonstrated linear elimination, dose-proportionality up to 1.8 mg/m(2) and time-independent pharmacokinetics. The pharmacokinetic impact of dexamethasone and sex covariates is probably limited given the moderate to large interindividual pharmacokinetic variability of trabectedin. The antiemetic and hepatoprotective effects are still a valid rationale to recommend dexamethasone as a supportive treatment for trabectedin.

Population Pharmacokinetic Modeling of Armodafinil and Its Major Metabolites.

Population pharmacokinetic models for armodafinil and its major metabolites, R-modafinil acid and modafinil sulfone, were developed, and selected covariates were investigated. Data from 583 healthy subjects and patients with bipolar I disorder in 11 phase 1-3 studies (8027 concentrations) of armodafinil, given as single or multiple once-daily doses (50- to 400-mg tablet or capsule), were pooled. A previously developed 1-compartment model with first-order absorption without covariate effects was initially applied to pooled phase 1 and 2 data. After covariate analysis, the phase 3 data were pooled with the phase 1 and 2 data set and the model was refined again using a second backward elimination step. Population modeling was performed with NONMEM version 7 with the first-order conditional estimation method. Estimated armodafinil apparent oral clearance (CL/F), volume of distribution (Vc/F), and absorption t½ were 2.01 L/h, 45 L, and 0.226 hours, respectively. Armodafinil CL/F and Vc/F increased with weight; predicted steady-state area under the curve was 16.4% higher and 29.1% lower in a patient weighing 50 or 150 kg, respectively, relative to a 70-kg patient. Female participants had 10.2% lower armodafinil Vc/F compared with male participants. Age, race (white vs nonwhite), health status (healthy vs bipolar I disorder), liver function, and renal function were not statistically significant predictors of armodafinil pharmacokinetics. CL/F and Vc/F for R-modafinil acid and modafinil sulfone were 16.7 L/h and 8.95 L and 6.82 L/h and 12.4 L, respectively. Weight did not affect exposure of either metabolite. These population pharmacokinetic models were from the largest population of adults reported to date and provide a robust characterization of the pharmacokinetics of armodafinil, R-modafinil acid, and modafinil sulfone in adults.

Prediction of efficacy for conversion from adjunctive therapy to monotherapy with eslicarbazepine acetate 800 mg once daily for partial-onset epilepsy.

PURPOSE: Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED) indicated for partial-onset seizures (POS). Clinical studies of gradual conversion to ESL 1,200 and 1,600 mg QD monotherapies were previously conducted in patients with POS who were not well-controlled by 1 or 2 AEDs. This report describes modeling and simulation of plasma eslicarbazepine (primary active metabolite of ESL) concentrations and time to monotherapy study exit to predict efficacy for conversion to ESL monotherapy at a lower dose of 800 mg, as an option for patients requiring or not tolerating higher doses since this regimen is effective in adjunctive therapy for POS. PATIENTS AND METHODS: A previously developed population pharmacokinetic model for ESL monotherapy was used to predict minimum plasma eslicarbazepine concentration (Cmin) in 1,500 virtual patients taking 1 (n=1,000) or 2 (n=500) AEDs at baseline, treated with ESL 400 mg QD for 1 week, followed by 800 mg QD for 17 weeks (similar to ESL monotherapy trials where the other AEDs were withdrawn during the first 6 weeks following titration to the randomized ESL dose). Model-predicted Cmin as a time-varying covariate and number of baseline AEDs were used to determine the weekly probability of each patient meeting exit criteria (65.3% threshold) indicative of worsening seizure control in 500 simulated ESL monotherapy trials. A previously developed extended Cox proportional hazards exposure-response model was used to relate time-varying eslicarbazepine exposure to the time to study exit. RESULTS: For virtual patients receiving ESL monotherapy (800 mg QD), the 95% upper prediction limit for exit rate at 112 days of 34.9% in patients taking 1 AED at baseline was well below the 65.3% threshold from historical control trials, while the estimate for patients taking 2 AEDs (70.6%) was slightly above the historical control threshold. CONCLUSION: This model-based assessment supports conversion to ESL 800 mg QD monotherapy for POS in adults taking 1 AED. For patients taking 2 concomitant AEDs, however, prescribers should consider maintenance doses of 1,200 or 1,600 mg ESL QD to reduce the likelihood of seizure worsening if conversion to ESL monotherapy is contemplated.