Pharmacokinetics, Safety, and Tolerability of Once-Daily Darunavir With Cobicistat and Weekly Isoniazid/Rifapentine.

BACKGROUND: Once-weekly isoniazid with rifapentine (HP) for 3 months is a recommended treatment for latent tuberculosis infection in persons with HIV. HP reduces exposures of certain antiretroviral medications, resulting in limited options for the concomitant use of these therapies. Here, we examined the pharmacokinetics (PK), safety, and tolerability of darunavir/cobicistat with HP. METHODS: This was an open-label, fixed sequence, two-period crossover study in persons without HIV. Participants received darunavir 800 mg/cobicistat 150 mg once-daily alone for 4 days, then continued darunavir/cobicistat once-daily for days 5-19 with HP coadministration on days 5, 12, and 19. Intensive PK assessments were performed on days 4, 14, and 19. PK parameters were determined using noncompartmental methods. Geometric mean ratios with 90% confidence intervals (CIs) were calculated and compared between phases using mixed-effects models. RESULTS: Thirteen participants were enrolled. Two withdrew after day 4, and one withdrew after day 14. Of the 3 withdrawals, 2 were attributed to drug-related adverse events. Darunavir area under the concentration-time curve, maximum concentrations (Cmax), and concentrations at 24 hours postdose (C24h) were reduced by 71%, 41%, and 96% ∼48-72 hours after HP administration (day 14), respectively, and 36%, 17%, and 89% with simultaneous HP administration (day 19), respectively. On day 14, 45% of the predose and 73% of C24h concentrations were below the darunavir EC50 (0.055 µg/mL). CONCLUSIONS: Darunavir exposures were significantly decreased with HP coadministration. Temporal relationships between HP coadministration and the extent of induction or mixed inhibition/induction of darunavir metabolism were apparent. Coadministration of darunavir/cobicistat with 3HP should be avoided.

Leveraging patient-centric sampling for clinical drug development and decentralized clinical trials: Promise to reality.

Advances in the technologies to enable patient-centric sampling (PCS) have the potential to improve blood sample collection by enabling clinical trial participants to collect samples via self-collection or with the help of a caregiver in their home. Typically, blood samples to assess pharmacokinetics and pharmacodynamics of a drug during clinical development are collected at a clinical site via venous blood draw. In this position paper by the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), the potential value PCS can bring to patients, to the clinical datasets generated, and to clinical trial sponsors is discussed, along with considerations for program decision making, bioanalytical feasibility, operations, and regulatory implications. With an understanding of the value of PCS and considerations when implementing during clinical drug development, we can bring the promise of PCS closer to reality and enable decentralized clinical trials.

Quantitative Benefit-Risk Assessment of P-gp-Mediated Drug-Drug Interactions of Dabigatran Coadministered With Pharmacokinetic Enhancers in Patients With Renal Impairment.

Drug-drug interactions (DDIs) between dabigatran and ritonavir/cobicistat are of major concern in people living with HIV, particularly in those with impaired renal function, because they can result in increased dabigatran exposure and thus an increased risk of major bleeding events. However, the extent of this interaction and subsequent need for dose adjustment in subjects with varying degrees of renal function is currently not yet fully understood. To close this knowledge gap, we conducted an integrated population physiologically-based pharmacokinetic/pharmacodynamic analysis linking changes in dabigatran exposure due to DDIs and varying degrees of renal function to the probability of experiencing an ischemic stroke or major bleeding event within 1 year. The results of our analysis suggest that coadministration of dabigatran etexilate (dabigatran prodrug) and ritonavir/cobicistat should be avoided in subjects with severe renal impairment. A 2-hour dose separation or dabigatran etexilate dose reduction to 110 mg b.i.d. (twice daily) should be considered in subjects with moderate renal impairment when coadministered with ritonavir, while the dabigatran etexilate dose should be further reduced to 75 mg b.i.d. when coadministered with cobicistat. No dabigatran etexilate dose adjustment is needed in subjects with normal renal function receiving ritonavir, but dabigatran etexilate dose reduction to 110 mg b.i.d. should be considered when coadministered with cobicistat.

A Novel Encochleated Formulation Improves Atovaquone Activity in a Murine Model of Pneumocystis Pneumonia.

Although atovaquone is effective in treating and preventing Pneumocystis pneumonia (PCP), its use is limited by nonlinear absorption and adverse events. The current study was undertaken to examine the activity of encochleated atovaquone (eATQ), a novel lipid-crystal nanoparticle formulation, in a mouse model of PCP. eATQ 100-200 mg was superior to commercially available atovaquone at 14 days in decreasing total Pneumocystis nuclei and asci. eATQ plus anidulafungin reduced nuclei significantly better than commercial atovaquone plus anidulafungin. eATQ is a novel formulation of atovaquone that warrants further evaluation for treatment and prevention of PCP.

A prospective evaluation on the interaction of fluconazole and voriconazole on serum concentrations of budesonide in patients treated for gastrointestinal GVHD.

The gastrointestinal (GI) tract is commonly affected by acute and chronic graft-versus-host disease (GVHD) in patients who have undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT). For patients developing GI GVHD, nonabsorbable corticosteroids such as budesonide may be used alone to reduce the risk of systemic corticosteroid toxicities or combined with systemic steroids to enhance clinical responses and to allow more rapid tapering of systemic corticosteroid doses. This prospective crossover study was conducted to evaluate what effect two commonly used antifungal agents, fluconazole, and voriconazole, would have on the trough (Cmin) and peak (Cmax) levels of budesonide in adult patients who had undergone allo-HSCT who subsequently developed clinical GI GVHD. Fifteen subjects were enrolled and nine completed the study and were evaluable. When coadministered with budesonide, voriconazole significantly increased the geometric mean of budesonide Cmin and Cmax levels by 8.52- and 6.63-fold, respectively. The cohort to evaluate the interaction with fluconazole did not meet accrual goals to reach definitive conclusions. In conclusion, this prospective study demonstrated that when patients with GI GVHD are treated with budesonide concurrently with voriconazole, the systemic concentrations of budesonide increase substantially which could increase the risk of steroid-associated toxicities.

Perioperative duloxetine as part of a multimodal analgesia regime reduces postoperative pain in lumbar canal stenosis surgery: a randomized, triple blind, and placebo-controlled trial

Background@#Duloxetine is an antidepressant that is also useful in chronic neuropathic and central origin pain. In this study, the role of duloxetine in decreasing acute postoperative pain after lumbar canal stenosis surgery is explored. @*Methods@#In this single center, triple blinded, and placebo-controlled trial, 96 patients were randomized for statistical analysis. The intervention group received oral duloxetine 30 mg once a day (OD) for 2 days before surgery, 60 mg OD from the day of surgery to the postoperative second day and 30 mg OD for the next 2 days (a total duration of 7 days). A placebo capsule was given in the other group for a similar time and schedule. The same standard perioperative analgesia protocols were followed in both groups. @*Results@#Total morphine consumption up to 24 hours was significantly decreased in the duloxetine group (p < 0.01). The time to the first analgesia requirement was similar in both groups but the time to the second and third dose of rescue analgesia increased significantly in the duloxetine group. The time to ambulation was decreased significantly (p < 0.01) in the duloxetine group as compared to the placebo group. Pain scores remained similar during most of the time interval. No significant difference was observed in the complication rate and patient satisfaction score recorded. @*Conclusions@#Duloxetine reduces postoperative pain after lumbar canal stenosis surgery with no increase in adverse effects.

Atypical Presentation of Viral Gastroenteritis in a Three-year-old Child Due to a UNC80 Mutation.

We report a three-year-old child with a rare genetic phenomenon, a UNC80 mutation, who had an unusual presentation of viral gastroenteritis. The UNC80 gene encodes for an important voltage-independent channel in neurons and a mutation in this protein can lead to severe hypotonia. The hypotonia manifests as delayed gastric emptying, impaired respiratory clearance, and/or delayed muscle coordination, which can predispose to infection susceptibility. UNC80 gene mutations have also been shown to cause global developmental delays, failure to thrive, and phenotypic dysmorphisms. In our patient, we believe that his genetic defect precipitated a complicated hospital course. The patient's delayed gastric emptying caused difficulty in recovering from viral gastroenteritis while a concurrent pneumonia diagnosis required assistance in clearing respiratory contents. The UNC80 mutation is under-studied, and more studies are necessary to understand the clinical implications of its phenotypes.

Immune regulation by glucocorticoids can be linked to cell type-dependent transcriptional responses.

Glucocorticoids remain the most widely used immunosuppressive and anti-inflammatory drugs, yet substantial gaps exist in our understanding of glucocorticoid-mediated immunoregulation. To address this, we generated a pathway-level map of the transcriptional effects of glucocorticoids on nine primary human cell types. This analysis revealed that the response to glucocorticoids is highly cell type dependent, in terms of the individual genes and pathways affected, as well as the magnitude and direction of transcriptional regulation. Based on these data and given their importance in autoimmunity, we conducted functional studies with B cells. We found that glucocorticoids impair upstream B cell receptor and Toll-like receptor 7 signaling, reduce transcriptional output from the three immunoglobulin loci, and promote significant up-regulation of the genes encoding the immunomodulatory cytokine IL-10 and the terminal-differentiation factor BLIMP-1. These findings provide new mechanistic understanding of glucocorticoid action and emphasize the multifactorial, cell-specific effects of these drugs, with potential implications for designing more selective immunoregulatory therapies.

Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum.

PURPOSE: PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth. METHODS: Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy. RESULTS: Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of -7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently. CONCLUSION: This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk-benefit evaluations for sirolimus treatment in PROS.

Mononuclear phagocyte system function and nanoparticle pharmacology in obese and normal weight ovarian and endometrial cancer patients.

PURPOSE: Obesity may alter mononuclear phagocyte system (MPS) function and the pharmacology and efficacy of nanoparticles therapies, such as PEGylated liposomal doxorubicin (PLD). We aimed to evaluate the relationships between hormone and chemokine mediators of MPS function and the pharmacokinetic (PK) exposure of PLD in obese and normal weight patients with ovarian and endometrial cancer. METHODS: Hormone and chemokine mediators in obese and normal weight ovarian and endometrial cancer patients were measured. A separate pharmacology study was performed that evaluated the relationship between serum hormone concentrations, MPS function, and PK disposition of PLD in refractory ovarian cancer patients. RESULTS: Univariate analysis revealed a significant relationship between serum estradiol and body mass index (OR 8.64, 95% CI 2.67-28.0, p < 0.001). Estrone and testosterone concentrations were positively correlated with MPS function (ρ = 0.57 and 0.53, p = 0.14 and 0.18, respectively) and inversely correlated with PLD PK exposure (ρ = - 0.75 and - 0.76, respectively, p = 0.02 for both). CONCLUSIONS: Higher MPS function resulting in reduced PLD exposure is a potential mechanism for reduced efficacy of PLD and other nanoparticles observed in obese patients with cancer. PK simulations suggest higher doses of PLD are required in obese patients to achieve similar exposures as standard dosing in normal weight patients.

Long-term use of continuous subcutaneous hydrocortisone infusion therapy in patients with congenital adrenal hyperplasia.

BACKGROUND: In a phase 2 short-term (6 months) study of patients with congenital adrenal hyperplasia (CAH), continuous subcutaneous hydrocortisone infusion (CSHI) was found to be a safe, effective and well-tolerated method of replacing cortisol with improved disease and patient-related outcomes. OBJECTIVE: To evaluate the safety and efficacy of long-term CSHI. DESIGN: Single-centre, open-label, phase 2 extension study. PATIENTS: Five adults with classic CAH. MEASUREMENTS: Biomarkers of disease control, metabolic indices and health-related quality-of-life (HRQoL) estimates. RESULTS: Six of eight patients chose to continue on long-term CSHI therapy. Compared to baseline, eighteen months of CSHI resulted in decreased (P = 0.043) 0700-hour ACTH, 17-hydroxyprogesterone, androstenedione and progesterone; increased whole-body lean mass (P = 0.024); and improved HRQoL, especially symptoms of adrenal insufficiency (P = 0.003). Findings at six and eighteen months did not differ, and improvements achieved in androgen control, lean body mass and HRQoL after 6 months of CSHI were maintained at eighteen months. The hydrocortisone dose appeared to decrease with time [6 vs 18 months: 38.3 ± 8.8 vs 33.6 ± 12.2 mg/day (P = 0.062)], especially in women receiving oral contraceptives. Reduction of testicular adrenal rest and adrenal size observed at 6 months remained stable. In one patient, an adrenal adenoma continually decreased over time. Subjective improvement in hirsutism was reported. CONCLUSIONS: Long-term use of CSHI is a safe and well-tolerated treatment option in a select set of adults with classic CAH. Improvements observed short term in disease control and subjective health status continued long term.

Potential Influence of Centrally Acting Herbal Drugs on Transporters at the Blood-Cerebrospinal Fluid Barrier and Blood-Brain Barrier.

Complementary and alternative medications (CAM) with known or suspected pharmacologic activity in the central nervous system (CNS) are common. These herbal preparations may cause clinically significant drug-drug interactions (DDIs) when coadministered with medications that act in the CNS. This can result in negative outcomes such as toxicity or loss of efficacy. Most drug interaction reports with CAM focus on cytochrome P450 (CYP) modulation. However, drug interactions between CAM and conventional medications may occur via mechanisms other than CYP inhibition or induction; in particular, modulation of drug transport proteins represents an important mechanism by which such interactions may occur. This article provides an updated review of transporter-mediated mechanisms by which herbal products may theoretically interact with centrally acting medications at the blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier. Further research is required before the true clinical impact of interactions involving modulation of centrally located membrane transporters can be fully understood.

JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies.

BACKGROUND: Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS: Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS: Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION: Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment. TRIAL REGISTRATION: ClinicalTrials.gov NCT01724580 and NCT02974595. FUNDING: This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

Cytokine-Mediated Systemic Adverse Drug Reactions in a Drug-Drug Interaction Study of Dolutegravir With Once-Weekly Isoniazid and Rifapentine.

Background: Once-weekly isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection. This study aimed to examine pharmacokinetic drug-drug interactions between this regimen and dolutegravir, a first-line antiretroviral medication. Methods: This was a single-center, open-label, fixed-sequence, drug-drug interaction study in healthy volunteers. Subjects received oral dolutegravir 50 mg once daily alone (days 1-4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (days 5-19). Dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and isoniazid concentrations were measured on day 19. Cytokines and antidrug antibodies to isoniazid and rifapentine were examined at select time points. Results: The study was terminated following the development of flu-like syndrome and elevated aminotransferase levels in 2 of 4 subjects after the third isoniazid-rifapentine dose. Markedly elevated levels of interferon-γ, CXCL10, C-reactive protein, and other cytokines were temporally associated with symptoms. Antidrug antibodies were infrequently detected. Dolutegravir area under the curve (AUC) was decreased by 46% (90% confidence interval, 27-110%; P = .13) on day 14. Rifapentine and 25-desacetyl rifapentine levels on day 19 were comparable to reference data, whereas isoniazid AUCs were approximately 67%-92% higher in the subjects who developed toxicities. Conclusions: The combined use of dolutegravir with once-weekly isoniazid-rifapentine resulted in unexpected and serious toxicities that were mediated by endogenous cytokine release. Additional investigations are necessary to examine the safety and efficacy of coadministering these medications. Clinical Trials Registration: NCT02771249.

Safety and tolerability of a novel, polyclonal human anti-MERS coronavirus antibody produced from transchromosomic cattle: a phase 1 randomised, double-blind, single-dose-escalation study.

BACKGROUND: Middle East respiratory syndrome (MERS) is a severe respiratory illness with an overall mortality of 35%. There is no licensed or proven treatment. Passive immunotherapy approaches are being developed to prevent and treat several human medical conditions where alternative therapeutic options are absent. We report the safety of a fully human polyclonal IgG antibody (SAB-301) produced from the hyperimmune plasma of transchromosomic cattle immunised with a MERS coronavirus vaccine. METHODS: We did a phase 1 double-blind, placebo-controlled, single-dose escalation trial at the National Institutes of Health Clinical Center. We recruited healthy participants aged 18-60 years who had normal laboratory parameters at enrolment, a body-mass index of 19-32 kg/m2, and a creatinine clearance of 70 mL/min or more, and who did not have any chronic medical problems that required daily oral medications, a positive rheumatoid factor (≥15 IU/mL), IgA deficiency (<7 mg/dL), or history of allergy to intravenous immunoglobulin or human blood products. Participants were randomly assigned by a computer-generated table, made by a masked pharmacist, to one of six cohorts (containing between three and ten participants each). Cohorts 1 and 2 had three participants, randomly assigned 2:1 to receive active drug SAB-301 versus normal saline placebo; cohorts 3 and 4 had six participants randomised 2:1; and cohorts 5 and 6 had ten participants, randomised 4:1. Participants received 1 mg/kg, 2·5 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, or 50 mg/kg of SAB-301, or equivalent volume placebo (saline control), on day 0, and were followed up by clinical, laboratory, and pharmacokinetic assessments on days 1, 3, 7, 21, 42, and 90. The primary outcome was safety, and immunogenicity was a secondary outcome. We analysed the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02788188. FINDINGS: Between June 2, 2016, and Jan 4, 2017, we screened 43 participants, of whom 38 were eligible and randomly assigned to receive SAB-301 (n=28) or placebo (n=10). 97 adverse events were reported: 64 adverse events occurred in 23 (82%) of 28 participants receiving SAB-301 (mean 2·3 adverse events per participant). 33 adverse events occurred in all ten participants receiving placebo (mean 3·3 adverse events per participant). The most common adverse events were headache (n=6 [21%] in participants who received SAB-301 and n=2 [20%] in those receiving placebo), albuminuria (n=5 [18%] vs n=2 [20%]), myalgia (n=3 [11%] vs n=1 [10%]), increased creatine kinase (n=3 [11%] vs 1 [10%]), and common cold (n=3 [11%] vs n=2 [20%]). There was one serious adverse event (hospital admission for suicide attempt) in one participant who received 50 mg/kg of SAB-301. The area under the concentration-time curve (AUC) in the 50 mg/kg dose (27 498 µg × days per mL) is comparable to the AUC that was associated with efficacy in a preclinical model. INTERPRETATION: Single infusions of SAB-301 up to 50 mg/kg appear to be safe and well tolerated in healthy participants. Human immunoglobulin derived from transchromosomic cattle could offer a new platform technology to produce fully human polyclonal IgG antibodies for other medical conditions. FUNDING: National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Biomedical Advanced Research and Development Authority.

Safety, tolerability, and pharmacokinetics of radavirsen (AVI-7100), an antisense oligonucleotide targeting influenza a M1/M2 translation.

AIMS: The aims of the present study were to assess the safety, tolerability and pharmacokinetics of radavirsen following single ascending doses and multiple doses given as intravenous infusions in healthy adults. METHODS: A phase I safety and pharmacokinetic study of radavirsen was performed in healthy volunteers. The study was divided into two parts. The first was a single-ascending-dose study of five cohorts of eight subjects each, randomized 6:2 to receive single intravenous doses of radavirsen ranging from 0.5 mg kg-1 to 8 mg kg-1 or placebo. The second was a multiple-dose study of 16 subjects randomized 12:4 to receive 8 mg kg-1 or placebo once daily for 5 days. RESULTS: A total of 66 subjects were screened, and 56 subjects were dosed between 2013 and 2015. At least one adverse event occurred in 31/42 (74%) who received radavirsen, and 13/14 (93%) receiving placebo. The most common adverse events were headache and proteinuria, and were similar in incidence and severity among those receiving radavirsen or placebo. Single-dose pharmacokinetics demonstrated relatively linear and dose-proportional increases in maximal concentration and in area under the concentration-time curve from zero to 24 h (AUC0-24 ). At 8 mg kg-1 in the multiple-dose cohort, the day 4 geometric mean AUC0-24 was 57.9 µg*h ml-1 . CONCLUSION: Single infusions of radavirsen up to 8 mg kg-1 , and multi-dosing at 8 mg kg-1 once daily for 5 days, appear to be safe and well tolerated in healthy subjects. The multi-dose day 4 AUC0-24 in the present study was comparable with that associated with protection from viral infection in a preclinical ferret influenza model. Further evaluation of radavirsen for the treatment of influenza infections is warranted.