Pharmacokinetics of Tenofovir Alafenamide With Boosted Protease Inhibitors in Pregnant and Postpartum Women Living With HIV: Results From IMPAACT P1026s.

BACKGROUND: Tenofovir alafenamide (TAF) is a key component of HIV treatment, but pharmacokinetic data supporting the use of TAF during pregnancy are limited. In this study, we report pharmacokinetic, safety, and birth outcomes for TAF 25 mg with a boosted protease inhibitor in pregnant women living with HIV. METHODS: IMPAACT P1026s was a multicenter, nonrandomized, open-label, phase IV prospective study. Pregnant women living with HIV receiving TAF 25 mg with a boosted protease inhibitor were eligible. Intensive pharmacokinetic assessments were performed during the second and third trimesters and 6-12 weeks postpartum. Maternal and cord blood samples were collected at delivery. Infant washout samples were collected through 5-9 days postbirth. Comparisons of paired pharmacokinetic data between pregnancy and postpartum were made using geometric mean ratios (GMR) [90% confidence intervals (CIs)] and Wilcoxon signed-rank tests with P < 0.10 considered significant. RESULTS: Twenty-nine women were enrolled from the United States (median age 31 years and weight 84.5 kg during the third trimester; 48% Black, 45% Hispanic/Latina). TAF AUCtau did not significantly differ in the second [GMR 0.62 (90% CI: 0.29 to 1.34); P = 0.46] or third trimester [GMR 0.94 (90% CI: 0.63 to 1.39); P = 0.50] vs. postpartum and were comparable with historical data in nonpregnant adults. TAF was only quantifiable in 2/25 maternal delivery samples and below the limit of quantification in all cord blood and infant washout samples, likely because of the short half-life of TAF. CONCLUSION: TAF AUCtau did not significantly differ between pregnancy and postpartum. These findings provide reassurance as TAF use during pregnancy continues to expand.

Anakinra Treatment in Patients with Acute Kawasaki Disease with Coronary Artery Aneurysms: A Phase I/IIa Trial.

OBJECTIVES: To determine the safety, pharmacokinetics, and immunomodulatory effects of 2-6 weeks of anakinra therapy in patients with acute Kawasaki disease with a coronary artery aneurysm (CAA). STUDY DESIGN: We performed a Phase I/IIa dose-escalation study of anakinra (2-11 mg/kg/day) in 22 patients with acute Kawasaki disease with CAA. We measured interleukin (IL)-1RA concentrations after the first dose and trough levels up to study week 6. Markers of inflammation and coronary artery z-scores were assessed pretreatment and at 48 hours, 2 weeks, and 6 weeks after initiation of therapy. RESULTS: Up to 6 weeks of anakinra (up to 11 mg/kg/day) was safe and well tolerated by the 22 participants (median age, 1.1 years), with no serious adverse events attributable to the study drug. All participants were treated with intravenous immunoglobulin (IVIG), and 20 also received infliximab (10 mg/kg) before initiation of anakinra. Serum levels of IL-6, IL-8, and tumor necrosis factor α decreased similarly in patients with Kawasaki disease treated with IVIG, infliximab, and anakinra compared with age- and sex-matched patients with Kawasaki disease treated only with IVIG and infliximab. Anakinra clearance increased with illness day at diagnosis. Simulations demonstrated that more frequent intravenous (IV) dosing may result in more sustained concentrations without significantly increasing the peak concentration compared with subcutaneous (SC) dosing. CONCLUSIONS: Both IV and SC anakinra are safe in infants and children with acute Kawasaki disease and CAA. IV dosing every 8-12 hours during the acute hospitalization of patients with Kawasaki disease may result in a sustained concentration while avoiding frequent SC injections. The efficacy of a short course of IV therapy during hospitalization should be studied. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT02179853.

Short-course Benznidazole treatment to reduce Trypanosoma cruzi parasitic load in women of reproductive age (BETTY): a non-inferiority randomized controlled trial study protocol.

BACKGROUND: Retrospective observational studies suggest that transmission of Trypanosoma cruzi does not occur in treated women when pregnant later in life. The level of parasitemia is a known risk factor for congenital transmission. Benznidazole (BZN) is the drug of choice for preconceptional treatment to reduce parasitic load. The fear of treatment-related side effects limits the implementation of the Argentine guideline recommending BZN 60d/300 mg (or equivalent) treatment of T. cruzi seropositive women during the postpartum period to prevent transmission in a future pregnancy. A short and low dose BZN treatment might reduce major side effects and increase compliance, but its efficacy to reduce T. cruzi parasitic load compared to the standard 60d/300 mg course is not yet established. Clinical trials testing alternative BZN courses among women of reproductive age are urgently needed. METHODS AND DESIGN: We are proposing to perform a double-blinded, non-inferiority randomized controlled trial comparing a short low dose 30-day treatment with BZN 150 mg/day (30d/150 mg) vs. BZN 60d/300 mg. We will recruit not previously treated T. cruzi seropositive women with a live birth during the postpartum period in Argentina, randomize them at 6 months postpartum, and follow them up with the following specific aims: Specific aim 1: to measure the effect of BZN 30d/150 mg compared to 60d/300 mg preconceptional treatment on parasitic load measured by the frequency of positive Polymerase Chain Reaction (PCR) (primary outcome) and by real-time quantitative PCR (qPCR), immediately and 10 months after treatment. Specific aim 2: to measure the frequency of serious adverse events and/or any adverse event leading to treatment interruption. TRIAL REGISTRATION: ClinicalTrials.gov . Identifier: NCT03672487 . Registered 14 September 2018.

Electronic Health Records and Pharmacokinetic Modeling to Assess the Relationship between Ampicillin Exposure and Seizure Risk in Neonates.

OBJECTIVE: To evaluate the relationship between ampicillin dosing, exposure, and seizures. STUDY DESIGN: This was a retrospective observational cohort study of electronic health record (EHR) data combined with pharmacokinetic model derived drug exposure predictions. We used the EHR from 348 Pediatrix Medical Group neonatal intensive care units from 1997 to 2012. We included all infants 24-41 weeks gestational age, 500-5400 g birth weight, first exposed to ampicillin prior to 25 days postnatal age. Using a 1-compartment pharmacokinetic model and EHR data, we simulated maximum ampicillin concentration at steady state (Cmaxss, µg/mL) and area under the concentration time curve from 0 to 24 hours (AUC24, µg*h/dL). Using multivariable logistic regression, we evaluated association between ampicillin dosing, exposure, and seizures as documented in the EHR. RESULTS: We identified 131 723 infants receiving 134 041 courses of ampicillin for 653 506 infant-days of exposure. The median daily dose was 200 mg/kg/d (25th, 75th percentile; 100, 200). Median Cmaxss and AUC24 were 256.6 µg/mL (164.3, 291.5) and 2593 µg*h/dL (1917, 3334). On multivariable analysis, dosing was not associated with seizures. However increasing Cmaxss (OR = 1.10, 95% CI 1.03, 1.17) and AUC24 (OR 1.11, 95% CI 1.05, 1.18) were associated with increased odds of seizures. CONCLUSIONS: In this cohort of hospitalized infants, higher ampicillin exposure was associated with seizures as documented in the EHR.

Pharmacokinetics of intravenous lorazepam in pediatric patients with and without status epilepticus.

OBJECTIVE: To evaluate the single dose pharmacokinetics of an intravenous dose of lorazepam in pediatric patients treated for status epilepticus (SE) or with a history of SE. STUDY DESIGN: Ten hospitals in the Pediatric Emergency Care Applied Research Network enlisted patients 3 months to 17 years with convulsive SE (status cohort) or for a traditional pharmacokinetics study (elective cohort). Sparse sampling was used for the status cohort, and intensive sampling was used for the elective cohort. Non-compartmental analyses were performed on the elective cohort, and served to nest compartmental population pharmacokinetics analysis for both cohorts. RESULTS: A total of 48 patients in the status cohort and 15 patients in the elective cohort were enrolled. Median age was 7 years, 2 months. The population pharmacokinetics parameters were: clearance, 1.2 mL/min/kg; half-life, 16.8 hours; and volume of distribution, 1.5 L/kg. On the basis of the pharmacokinetics model, a 0.1 mg/kg dose is expected to achieve concentrations of approximately 100 ng/mL and maintain concentrations >30 to 50 ng/mL for 6 to 12 hours. A second dose of 0.05 mg/kg would achieve desired therapeutic serum levels for approximately 12 hours without excessive sedation. Age-dependent dosing is not necessary beyond using a maximum initial dose of 4 mg. CONCLUSIONS: Lorazepam pharmacokinetics in convulsive SE is similar to earlier pharmacokinetics measured in pediatric patients with cancer, except for longer half-life, and similar to adult pharmacokinetics parameters except for increased clearance.

Infliximab treatment of intravenous immunoglobulin-resistant Kawasaki disease.

OBJECTIVE: To investigate the safety, tolerability, and pharmacokinetics of the anti-tumor necrosis factor-alpha monoclonal antibody infliximab in subjects with intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD). STUDY DESIGN: We conducted a multicenter, randomized, prospective trial of second IVIG infusion (2 g/kg) versus infliximab (5 mg/kg) in 24 children with acute KD and fever after initial treatment with IVIG. Primary outcome measures were the safety, tolerability, and pharmacokinetics of infliximab. Secondary outcome measures were duration of fever and changes in markers of inflammation. RESULTS: Study drug infusions were associated with cessation of fever within 24 hours in 11 of 12 subjects treated with infliximab and in 8 of 12 subjects retreated with IVIG. No infusion reactions or serious adverse events were attributed to either study drug. No significant differences were observed between treatment groups in the change from baseline for laboratory variables, fever, or echocardiographic assessment of coronary arteries. CONCLUSIONS: Both infliximab and a second IVIG infusion were safe and well tolerated in the subjects with KD who were resistant to standard IVIG treatment. The optimal management of patients resistant to IVIG remains to be determined.

Pharmacokinetics, safety and efficacy of lopinavir/ritonavir in infants less than 6 months of age: 24 week results.

OBJECTIVE: To investigate pharmacokinetics, safety and efficacy of lopinavir/ritonavir (LPV/r)-based therapy in HIV-1-infected infants 6 weeks to 6 months of age. METHODS: A prospective, multicenter, open-label trial of 21 infants with HIV-1 RNA > 10 000 copies/ml and treated with LPV/r 300/75 mg/m twice daily plus two nucleoside reverse transcriptase inhibitors. Intensive pharmacokinetic sampling was performed at 2 weeks and predose concentrations were collected every 8 weeks; safety and plasma HIV-1 RNA were monitored every 4-12 weeks for 24 weeks. RESULTS: Median age at enrollment was 14.7 weeks (range, 6.9-25.7) and 19/21 completed > or= 24 weeks of study. Although LPV/r apparent clearance was slightly higher than in older children, the median area under the concentration-time curve 0-12 h (67.5 mug.h/ml) was in the range reported from older children taking the recommended dose of 230/57.5 mg/m. Predose concentrations stabilized at a higher level after the first 2 weeks of study. In as-treated analysis at week 24, 10/19 (53%) had plasma HIV-1 RNA < 400 copies/ml (median change, -3.33 log10 copies/ml); poor adherence contributed to delayed viral suppression, which improved with longer follow-up. Three infants (14%) had transient adverse events of grade 3 or more that were possibly related to study treatment but did not require permanent treatment discontinuation. CONCLUSION: Despite higher clearance in infants 6 weeks to 6 months of age, a twice daily dose of 300/75 mg/m LPV/r provided similar exposure to that in older children, was well tolerated and provided favorable virological and clinical efficacy.

Pharmacokinetics and tolerance of zidovudine in preterm infants.

OBJECTIVE: To determine zidovudine pharmacokinetics and tolerance in premature human human immunodeficiency virus-exposed infants. STUDY DESIGN: Pediatric AIDS Clinical Trials Group Study 331 was a multicentered prospective, open-label study of the use of zidovudine in premature infants. Thirty-eight infants <35 weeks' gestational age (GA) were studied while receiving zidovudine 1.5 mg/kg every 12 hours until 2 weeks of age, then 2.0 mg/kg every 8 hours until 6 weeks of age. Population pharmacokinetics were evaluated at 1, 2, and 4 weeks' postnatal age; zidovudine doses were adjusted to maintain troughs <3 microM. RESULTS: Zidovudine clearance was lower than reported in term infants at similar postnatal ages. Nine premature infants required dose reduction because of high levels (7/19 <30 weeks' and 2/19 >/=30 weeks' GA). Postnatal age, GA, serum creatinine, and furosemide use independently predicted zidovudine clearance. Zidovudine was generally well tolerated in this high-risk population. CONCLUSIONS: Zidovudine clearance is greatly reduced in premature infants. We recommend the following zidovudine dosing schedule in this population: 1.5 mg/kg (intravenous) or 2.0 mg/kg (oral) every 12 hours increased to every 8 hours at 2 weeks of age (>/=30 weeks' GA) or at 4 weeks (<30 weeks' GA).