Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.

BACKGROUND: Congenital thrombotic thrombocytopenic purpura (TTP) results from severe hereditary deficiency of ADAMTS13. The efficacy and safety of recombinant ADAMTS13 and standard therapy (plasma-derived products) administered as routine prophylaxis or on-demand treatment in patients with congenital TTP is not known. METHODS: In this phase 3, open-label, crossover trial, we randomly assigned patients in a 1:1 ratio to two 6-month periods of prophylaxis with recombinant ADAMTS13 (40 IU per kilogram of body weight, administered intravenously) or standard therapy, followed by the alternate treatment; thereafter, all the patients received recombinant ADAMTS13 for an additional 6 months. The trigger for this interim analysis was trial completion by at least 30 patients. The primary outcome was acute TTP events. Manifestations of TTP, safety, and pharmacokinetics were assessed. Patients who had an acute TTP event could receive on-demand treatment. RESULTS: A total of 48 patients underwent randomization; 32 completed the trial. No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05). Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy). Adverse events occurred in 71% of the patients with recombinant ADAMTS13 and in 84% with standard therapy. Adverse events that were considered by investigators to be related to the trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in 48% with standard therapy. Trial-drug interruption or discontinuation due to adverse events occurred in no patients with recombinant ADAMTS13 and in 8 patients with standard therapy. No neutralizing antibodies developed during recombinant ADAMTS13 treatment. The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy. CONCLUSIONS: During prophylaxis with recombinant ADAMTS13 in patients with congenital TTP, ADAMTS13 activity reached approximately 100% of normal levels, adverse events were generally mild or moderate in severity, and TTP events and manifestations were rare. (Funded by Takeda Development Center Americas and Baxalta Innovations; ClinicalTrials.gov number, NCT03393975.).

Pharmacokinetics, Safety, and Tolerability of Imipenem/Cilastatin/Relebactam in Children with Confirmed or Suspected Gram-Negative Bacterial Infections: A Phase 1b, Open-Label, Single-Dose Clinical Trial.

Imipenem/cilastatin/relebactam is approved for the treatment of serious gram-negative bacterial infections in adults. This study assessed the pharmacokinetics (PK), safety, and tolerability of a single dose of imipenem/cilastatin/relebactam (with a fixed 2:1 ratio of imipenem/cilastatin to relebactam, and with a maximum dose of 15 mg/kg imipenem and 15 mg/kg cilastatin [≤500 mg imipenem and ≤500 mg cilastatin] and 7.5 mg/kg relebactam [≤250 mg relebactam]) in children with confirmed/suspected gram-negative bacterial infections receiving standard-of-care antibacterial therapy. In this phase 1, noncomparative study (ClinicalTrials.gov identifier, NCT03230916), PK parameters from 46 children were analyzed using both population modeling and noncompartmental analysis. The PK/pharmacodynamic (PD) target for imipenem was percent time of the dosing interval that unbound plasma concentration exceeded the minimum inhibitory concentration (%fT>MIC) of ≥30% (MIC = 2 mcg/mL). For relebactam, the PK/PD target was a free drug area under the plasma concentration-time curve (AUC) normalized to MIC (at 2 mcg/mL) of ≥8.0 (equivalent to an AUC from time zero extrapolated to infinity of ≥20.52 mcg·h/mL). Safety was assessed up to 14 days after drug infusion. For imipenem, the ranges for the geometric mean %fT>MIC and maximum concentration (Cmax ) across age cohorts were 56.5%-93.7% and 32.2-38.2 mcg/mL, respectively. For relebactam, the ranges of the geometric mean Cmax and AUC from 0 to 6 hours across age cohorts were 16.9-21.3 mcg/mL and 26.1-55.3 mcg·h/mL, respectively. In total, 8/46 (17%) children experienced ≥1 adverse events (AEs) and 2/46 (4%) children experienced nonserious AEs that were deemed drug related by the investigator. Imipenem and relebactam exceeded plasma PK/PD targets; single doses of imipenem/cilastatin/relebactam were well tolerated with no significant safety concerns identified. These results informed imipenem/cilastatin/relebactam dose selection for further pediatric clinical evaluation.

Imipenem/cilastatin/relebactam efficacy, safety and probability of target attainment in adults with hospital-acquired or ventilator-associated bacterial pneumonia among patients with baseline renal impairment, normal renal function, and augmented renal clearance.

Objectives: To assess the relationship between renal function and efficacy/safety of imipenem/cilastatin/relebactam for the treatment of hospital-acquired/ventilator-associated pneumonia (HABP/VABP) from RESTORE-IMI 2 and determine the PTA. Methods: Adults with HABP/VABP were randomized 1:1 to IV imipenem/cilastatin/relebactam 1.25 g or piperacillin/tazobactam 4.5 g every 6 h for 7-14 days. Initial doses were selected by CLCR and adjusted thereafter, as appropriate. Outcomes included Day 28 all-cause mortality (ACM), clinical response, microbiological response and adverse events. Population pharmacokinetic modelling and Monte Carlo simulations assessed PTA. Results: The modified ITT population comprised those with normal renal function (n = 188), augmented renal clearance (ARC; n = 88), mild renal impairment (RI; n = 124), moderate RI (n = 109) and severe RI (n = 22). ACM rates were comparable between treatment arms among all baseline renal function categories. Clinical response rates were comparable between treatment arms for participants with RI and normal renal function but were higher (91.7% versus 44.4%) for imipenem/cilastatin/relebactam-treated versus piperacillin/tazobactam-treated participants with CLCR ≥250 mL/min (n = 21). Microbiologic response rates were comparable between treatment arms for participants with RI but higher among those treated with imipenem/cilastatin/relebactam in participants with CLCR ≥90 mL/min (86.6% versus 67.2%). Adverse events were comparable between treatment arms across renal function categories. Joint PTA was >98% for key pathogen MICs for susceptible pathogens (MIC ≤2 mg/L). Conclusions: Prescribing information-defined dose adjustments in participants with baseline RI and full dosing of imipenem/cilastatin/relebactam 1.25 g every 6 h for participants with normal renal function or augmented renal clearance achieved sufficiently high drug exposures and favourable safety and efficacy profiles.

Safety and Pharmacokinetics of Islatravir in Individuals with Severe Renal Insufficiency.

Islatravir (MK-8591) is a high-potency reverse transcriptase translocation inhibitor in development for the treatment of HIV-1 infection. Data from preclinical and clinical studies suggest that ~30% to 60% of islatravir is excreted renally and that islatravir is not a substrate of renal transporters. To assess the impact of renal impairment on the pharmacokinetics of islatravir, an open-label phase 1 trial was conducted with individuals with severe renal insufficiency (RI). A single dose of islatravir 60 mg was administered orally to individuals with severe RI (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) and to healthy individuals without renal impairment (matched control group; eGFR ≥90 mL/min/1.73 m2). Safety and tolerability were assessed, and blood samples were collected to measure the pharmacokinetics of islatravir and its major metabolite 4'-ethynyl-2-fluoro-2'deoxyinosine (M4) in plasma, as well as active islatravir-triphosphate (TP) in peripheral blood mononuclear cells (PBMCs). Plasma islatravir and M4 area under the concentration-time curve from zero to infinity (AUC0-∞) were ~2-fold and ~5-fold higher, respectively, in participants with severe RI relative to controls, whereas islatravir-TP AUC0-∞ was ~1.5-fold higher in the RI group than in the control group. The half-lives of islatravir in plasma and islatravir-TP in PBMCs were longer in participants with severe RI than in controls. These findings are consistent with renal excretion playing a major role in islatravir elimination. A single oral dose of islatravir 60 mg was generally well tolerated. These data provide guidance regarding administration of islatravir in individuals with impaired renal function. (This study has been registered at ClinicalTrials.gov under registration no. NCT04303156.).

Population pharmacokinetic/pharmacodynamic assessment of imipenem/cilastatin/relebactam in patients with hospital-acquired/ventilator-associated bacterial pneumonia.

In the phase III RESTORE-IMI 2 study (ClinicalTrials.gov: NCT02493764), the combination antibacterial agent imipenem/cilastatin/relebactam (IMI/REL) demonstrated noninferiority to piperacillin/tazobactam for the end points of all-cause mortality at day 28 and favorable clinical response at the early follow-up visit in adult participants with gram-negative hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP). Existing population pharmacokinetic models for imipenem (IPM) and REL were updated using data from patients with HABP/VABP from RESTORE-IMI 2. Creatinine clearance (CrCl), body weight, infection type, and ventilation status were significant covariates in the updated model. The following simulations were performed to calculate the pharmacokinetic/pharmacodynamic joint probability of target attainment among patients with HABP/VABP and varying degrees of renal function: augmented renal clearance (CrCl ≥150 ml/min), normal renal function (CrCl ≥90 to <150 ml/min), renal impairment (mild, CrCl ≥60 to <90 ml/min; moderate, CrCl ≥30 to <60 ml/min; or severe, CrCl ≥15 to <30 ml/min), and end-stage renal disease (CrCl <15 ml/min). At the recommended IMI/REL dosing regimens across renal categories, greater than 90% of patients in all renal function groups were predicted to achieve joint pharmacokinetic/pharmacodynamic targets at a minimum inhibitory concentration breakpoint of ≤2 µg/ml, regardless of ventilation status. This modeling and simulation analysis supports use of the recommended IMI/REL dosing regimens, adjusted based on renal function, in patients with HABP/VABP.

Safety and pharmacokinetics of islatravir subdermal implant for HIV-1 pre-exposure prophylaxis: a randomized, placebo-controlled phase 1 trial.

Islatravir (MK-8591) is a highly potent type 1 human immunodeficiency virus (HIV-1) nucleoside reverse transcriptase translocation inhibitor with a long intracellular half-life that is in development for the prevention and treatment of HIV-1. We conducted a randomized, double-blind, placebo-controlled, phase 1 trial in adults without HIV-1 infection. Participants received islatravir or placebo subdermal implants for 12 weeks and were monitored throughout this period and after implant removal. The co-primary end points were safety and tolerability of the islatravir implant and pharmacokinetics, including concentration at day 85, of islatravir triphosphate in peripheral blood mononuclear cells (PBMCs). Secondary end points included additional pharmacokinetic parameters for islatravir triphosphate in PBMCs and the plasma pharmacokinetic profile of islatravir. Based on preclinical data, two doses were assessed: 54 mg (n = 8, two placebo) and 62 mg (n = 8, two placebo). The most frequently reported adverse events were mild-to-moderate implant-site reactions (induration, hematoma, pain). Throughout the 12-week trial, geometric mean islatravir triphosphate concentrations were above a pharmacokinetic threshold of 0.05 pmol per 106 PBMCs, which was estimated to provide therapeutic reverse transcriptase inhibition (concentration at day 85 (percentage of geometric coefficient of variation): 54 mg, 0.135 pmol per 106 cells (27.3); 62 mg, 0.272 pmol per 106 cells (45.2)). Islatravir implants at both doses were safe and resulted in mean concentrations above the pharmacokinetic threshold through 12 weeks, warranting further investigation of islatravir implants as a potential HIV prevention strategy.

In Vitro Pharmacokinetic/Pharmacodynamic Modeling of HIV Latency Reversal by Novel HDAC Inhibitors Using an Automated Platform.

Antiretroviral therapy is able to effectively control but not eradicate HIV infection, which can persist, leading to the need for lifelong therapy. The existence of latently HIV-infected cells is a major barrier to the eradication of chronic HIV infection. Histone deacetylase inhibitors (HDACis), small molecules licensed for oncology indications, have shown the ability to produce HIV transcripts in vitro and in vivo. The pharmacologic parameters that drive optimal HIV latency reversal in vivo are unknown and could be influenced by such factors as the HDACi binding kinetics, concentration of compound, and duration of exposure. This study evaluates how these parameters affect HIV latency reversal for a series of novel HDACis that differ in their enzymatic on and off rates. Varying cellular exposure, using automated washout methods of HDACi in a Jurkat cell model of HIV latency, led to the investigation of the relationship between pharmacokinetic (PK) properties, target engagement (TE), and pharmacodynamic (PD) responses. Using an automated robotic platform enabled miniaturization of a suspension cell-based washout assay that required multiple manipulations over the 48 h duration of the assay. Quantification of histone acetylation (TE) revealed that HDACis showed early peaks and differences in the durability of response between different investigated HDACis. By expanding the sample times, the shift between TE and PD, as measured by green fluorescent protein, could be fully characterized. The comprehensive data set generated by automating the assays described here was used to establish a PK/PD model for HDACi-induced HIV latency reversal.

A Randomized, Double-blind, Multicenter Trial Comparing Efficacy and Safety of Imipenem/Cilastatin/Relebactam Versus Piperacillin/Tazobactam in Adults With Hospital-acquired or Ventilator-associated Bacterial Pneumonia (RESTORE-IMI 2 Study).

BACKGROUND: Imipenem combined with the ß-lactamase inhibitor relebactam has broad antibacterial activity, including against carbapenem-resistant gram-negative pathogens. We evaluated efficacy and safety of imipenem/cilastatin/relebactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). METHODS: This was a randomized, controlled, double-blind phase 3 trial. Adults with HABP/VABP were randomized 1:1 to imipenem/cilastatin/relebactam 500 mg/500 mg/250 mg or piperacillin/tazobactam 4 g/500 mg, intravenously every 6 hours for 7-14 days. The primary endpoint was day 28 all-cause mortality in the modified intent-to-treat (MITT) population (patients who received study therapy, excluding those with only gram-positive cocci at baseline). The key secondary endpoint was clinical response 7-14 days after completing therapy in the MITT population. RESULTS: Of 537 randomized patients (from 113 hospitals in 27 countries), the MITT population comprised 264 imipenem/cilastatin/relebactam and 267 piperacillin/tazobactam patients; 48.6% had ventilated HABP/VABP, 47.5% APACHE II score ≥15, 24.7% moderate/severe renal impairment, 42.9% were ≥65 years old, and 66.1% were in the intensive care unit. The most common baseline pathogens were Klebsiella pneumoniae (25.6%) and Pseudomonas aeruginosa (18.9%). Imipenem/cilastatin/relebactam was noninferior (P < .001) to piperacillin/tazobactam for both endpoints: day 28 all-cause mortality was 15.9% with imipenem/cilastatin/relebactam and 21.3% with piperacillin/tazobactam (difference, -5.3% [95% confidence interval {CI}, -11.9% to 1.2%]), and favorable clinical response at early follow-up was 61.0% and 55.8%, respectively (difference, 5.0% [95% CI, -3.2% to 13.2%]). Serious adverse events (AEs) occurred in 26.7% of imipenem/cilastatin/relebactam and 32.0% of piperacillin/tazobactam patients; AEs leading to treatment discontinuation in 5.6% and 8.2%, respectively; and drug-related AEs (none fatal) in 11.7% and 9.7%, respectively. CONCLUSIONS: Imipenem/cilastatin/relebactam is an appropriate treatment option for gram-negative HABP/VABP, including in critically ill, high-risk patients. CLINICAL TRIALS REGISTRATION: NCT02493764.

A Single- and Multiple-Dose Study To Characterize the Pharmacokinetics, Safety, and Tolerability of Imipenem and Relebactam in Healthy Chinese Participants.

Relebactam/imipenem/cilastatin is approved in the United States to treat complicated urinary tract and intra-abdominal infections in patients who have limited or no alternative treatment options and hospital-acquired bacterial pneumonia (HABP)/ventilator-associated bacterial pneumonia (VABP). Initial pharmacokinetic, safety, and tolerability studies of relebactam with and without imipenem/cilastatin included mostly Caucasian participants. This study evaluated the pharmacokinetics, safety, and tolerability of relebactam/imipenem/cilastatin in 12 healthy Chinese participants after three single doses of increasing concentrations (relebactam at 125, 250, or 500 mg; cilastatin at 250, 500, or 1,000 mg; and imipenem at 250, 500, or 1,000 mg) and after multiple doses every 6 h of a single concentration (relebactam at 250 mg, cilastatin at 500 mg, and imipenem at 500 mg) for 14 days. After single doses, the area under the concentration-time curve (AUC) extrapolated to infinity (relebactam, 15.0 to 70.7 h · mg/liter; imipenem, 24.1 to 109.8 h · mg/liter; cilastatin, 18.4 to 95.3 h · mg/liter) and the AUC from 0 to 6 h (relebactam, 14.2 to 66.3 h · mg/liter; imipenem, 23.4 to 107.3 h · mg/liter; cilastatin, 18.3 to 94.4 h · mg/liter) increased in a dose-dependent manner; clearance (relebactam, 6.9 to 8.3 liters/h; imipenem, 8.6 to 10.4 liters/h; cilastatin, 10.5 to 13.6 liters/h) and half-life (relebactam, 1.4 to 1.6 h; imipenem, 1.0 to 1.2 h; cilastatin, 0.7 to 1.0 h) were consistent between doses. Pharmacokinetic parameters after multiple doses were similar to parameters after a single dose (geometric mean ratios of 0.8 to 1.0 for all three agents). Relebactam/imipenem/cilastatin was well tolerated; mild adverse events occurred during single dosing, and one participant experienced serious adverse events after multiple doses. Pharmacokinetics and safety data are comparable with data from participants of other ethnicities, supporting the use of relebactam/imipenem/cilastatin at the approved dose and schedule in Chinese patients.

Effective expansion of alloantigen-specific Foxp3+ CD25+ CD4+ regulatory T cells by dendritic cells during the mixed leukocyte reaction.

Thymic-derived CD25+ CD4+ T regulatory cells (Tregs) suppress immune responses, including transplantation. Here we evaluated the ability of dendritic cells (DCs) to expand alloantigen-specific Tregs in the mixed leukocyte reaction (MLR) that develops from polyclonal populations of T cells. The allogeneic DCs, when supplemented with IL-2 in the cultures, were much more effective than bulk spleen cells in expanding the numbers of Tregs. Likewise, DCs and not spleen cells were effective in sustaining expression of the transcription factor Foxp3 in Tregs, but neither IL-2 nor CD80/86 was required for this effect in the cultures. On a per-cell basis, the DC-expanded, but not unexpanded, Tregs were more potent suppressors of a fresh MLR by CD25- CD4+ T cells. Suppression was 3- to 10-fold more active for MLRs induced by the original alloantigens than for third-party stimulators. When DC-expanded Tregs were introduced into sublethally irradiated hosts, the T cells suppressed graft-versus-host-disease induced by CD25- CD4+ T cells. Again, suppression was more active against the same mouse strain that provided the DCs to expand the Tregs. Therefore, alloantigen-selected Tregs are more effective suppressors of responses to major transplantation antigens, and these Tregs can be expanded from a polyclonal repertoire by DCs.

Combined hard palate spacer graft, midface suspension, and lateral canthoplasty for lower eyelid retraction: a tripartite approach.

BACKGROUND: Eyelid retraction is an unfortunate consequence of cosmetic surgery, trauma, and disease states. It is frequently symptomatic and may be associated with dry eye syndrome and corneal compromise. The pathophysiology of lower eyelid retraction usually involves some degree of lateral canthal tendon laxity, middle lamella scarring, and malar descent. The authors describe for the first time a series of patients whose lid retraction was treated with a tripartite procedure that addresses all three pathophysiologic components simultaneously and rehabilitates the patients cosmetically and functionally. METHODS: The authors retrospectively reviewed the records of 17 patients (24 eyelids) operated on between 1999 and 2003 by one senior surgeon. The age of the patients ranged from 26 to 77 years (mean, 50.3 years), and all presented with significant scleral show (average, 2.0 mm) and symptomatic corneal exposure from a variety of causes. Preoperatively, all patients were noted to have a combination of lower eyelid laxity, middle lamellar contracture, and malar descent. Preoperative and postoperative examinations included Shirmer's test, a measurement of scleral show, and a slit-lamp examination. Mean follow-up time was 13 months. All patients underwent a triad of hard palate spacer grafting, lateral canthal suspension, and midface elevation. RESULTS: All 17 patients (representing 24 retracted eyelids) had complete resolution of scleral show (2.5-mm average correction) and were uniformly satisfied with their cosmetic and functional outcome at last follow-up. Preoperative dry eye symptoms resolved in all patients in the series. There were no major complications and only two minor complications (corneal irritation from graft sutures in one patient and an oronasal palatal fistula in another), both of which resolved in the early follow-up period. CONCLUSIONS: The combination of hard palate spacer grafting, lateral canthoplasty, and midface suspension is an effective, aesthetic, and functional treatment for moderate to severe lower eyelid retraction resulting from multiple causes. This tripartite procedure is associated with predictable results, a low morbidity rate, and high patient satisfaction.

Botox and collagen for glabellar furrows: advantages of combination therapy.

Plastic surgeons frequently administer botulinum toxin A (Botox) or collagen as monotherapy to treat glabellar furrows. This study evaluates the possible advantages of combination therapy. Sixty-five patients with moderate to severe glabellar rhytids were prospectively randomized to receive standard injections of Botox, Zyderm II collagen, or a combination. Improvement in rhytids was assessed over 3 months using patient satisfaction scores and an independent physician evaluation. Baseline wrinkle severity was similar in all 3 groups. By 1 month posttreatment, the combination arm showed significantly greater improvement in furrows (79% compared with only 56% and 50% in the Botox and Zyderm arms, respectively; P < 0.05). At 3 months postinjection, the dual-therapy arm maintained better improvement (57% versus 33% and 27% in the monotherapy arms; P < 0.05). Patient satisfaction further highlighted the superiority of the combination approach. By simultaneously addressing the static and dynamic aspects of glabellar furrows, dual therapy provides optimal treatment of this problem.

COX-2 up-regulation in idiopathic carpal tunnel syndrome.

The objective of this study was to determine whether cyclooxygenase-2 (COX-2) is up-regulated in the synovium of patients with carpal tunnel syndrome. Twenty patients were enrolled: 16 consecutive patients with carpal tunnel syndrome and four control patients (exploration for non-carpal tunnel syndrome-related wrist or forearm pathology). Clinical data (demographics, pertinent history, symptomatology) were obtained preoperatively. Flexor tenosynovial tissue was isolated from all patients and clinically graded as thin, intermediate, or thick. Histologic evaluation was conducted to rule out the presence of inflammatory cells. Immunohistochemical staining for COX-2 was performed. The immunohistochemical data were confirmed by reverse transcriptase-polymerase chain reaction analysis of COX-2 mRNA. Results showed that the majority of carpal tunnel syndrome specimens (88 percent) showed synovial hypertrophy compared with 0 percent of the controls (p < 0.05). Also, 69 percent of carpal tunnel syndrome specimens (11 of 16) versus 0 percent of controls (zero of four) stained positively for COX-2 (p < 0.05). Of the carpal tunnel syndrome patients, 91 percent of thick specimens versus 33 percent of intermediate specimens versus 0 percent of thin specimens showed COX-2 staining. The authors conclude that synovial hypertrophy is a prominent finding in carpal tunnel syndrome. COX-2 is up-regulated in the tenosynovium of patients with carpal tunnel syndrome, and this upregulation may correlate with the clinical grade of the tenosynovium. The role of COX-2 in carpal tunnel syndrome may be to mediate remodeling of pathologic tissue. To this end, it may be a potential therapeutic target for specific inhibition.