Twice-daily Dosing Research Articles

Corticosteroid-LABA inhalers increase phonation threshold pressure (PTP) and flow (PTF) in rabbits.

This study examined the effects of a combination corticosteroid plus long-acting beta2 -adrenergic agonist inhaler (IC) on rabbit phonation. White New Zealand male rabbits were assigned randomly to experimental and control groups (n=11 per group). The experimental group received twice-daily doses of Advair HFA™ (fluticasone propionate 45 mcg and salmeterol 21 mcg) via a veterinary facemask with 1-way valve and spacer; the control group received aerosolized saline. After 8 weeks, animals were euthanized, larynges excised, frozen, and subsequently thawed and mounted on a standard bench apparatus. Phonation was elicited during 15 successive trials, and phonation threshold pressure (PTP; cmH2 O) and flow (PTF; L/min) were quantified. Repeated measures analysis of variance indicated significant differences between the experimental and control groups (p < 0.05). Mean PTP and PTF values were higher (worse) for rabbits that received Advair HFA™. Following 8-week exposure to ICs, rabbit larynges required greater air pressure and flow to initiate phonation. Because even modest phonation onset differences can have a meaningful clinical impact on voice function, these findings suggest that LABA ICs may put patients at risk for voice disorders. Furthermore, these voice disorders may occur within a relatively short timeframe. The results from this study have important clinical implications for voice care in those who use ICs. NA Laryngoscope, 133:2680-2686, 2023.

Management of infantile hemangiomas-experience of a tertiary hospital.

The purpose of the study is to describe the experience of a multidisciplinary team in a tertiary hospital regarding the management of Infantile Hemangiomas (IH). The method employed is a retrospective analysis of patients with IH followed in a tertiary pediatric hospital between January 2010 and May 2022. A total of 393 IH were diagnosed (56.7% female), with a median age of 5months (interquartile range (IQR), 3-10). Imaging investigation was necessary for diagnosis and for exclusion of other IH in 9.2% and 14.3%, respectively. Focal (74.0%) and superficial (59.7%) lesions were more frequent as was facial location (35.9%). Pre-treatment ulceration or hemorrhage occurred in 6.6%. At follow-up, 87.4% regressed partially and 12.6% completely; 2.7% relapsed. Propranolol was started in 30.0% of cases for a median period of 9months (IQR, 6-12), mainly due to esthetic concerns (41.9%). Side effects occurred in 8.3% (sleep disturbance in 5.1%). Only 1.7% were refractory and 5.9% had a rebound effect. Eleven patients were treated with topical timolol and 41 underwent surgery. Patients that were treated with propranolol had more risk factors (p = 0.016) and presented deeper lesions (p < 0.001) with a larger diameter (p < 0.001); total IH regression was less frequent (p < 0.001). Since 2020, twice-daily dosage was more frequently prescribed than three times daily (p = 0.007) and inpatient initiation of propranolol decreased (p = 0.750), without significant difference in the incidence of adverse reactions, duration of treatment, and lesion evolution. Conclusions: Our protocol proved to be safe and feasible in an outpatient setting and twice daily administration of propranolol was effective. The majority of IH showed at least partial regression. Early detection of high-risk IH is paramount and a multidisciplinary assessment by a specialized team is essential for adequate management. What is Known: • IH are the most common vascular tumors in childhood. Although the majority evolves favorably, treatment may be warranted in selected cases. • Early detection of high-risk IH is paramount, and a multidisciplinary assessment by a specialized team is essential for adequate management. What is New: • One-third of our sample was treated with propranolol. These patients had more risk factors and presented deeper lesions with a larger diameter, and tumor total regression was less frequent. • Our results reinforce safety and feasibility of propranolol initiation in an outpatient setting, including twice daily dosage.

Pharmacokinetics, pharmacodynamics, safety and tolerability of cilofexor, a novel nonsteroidal Farnesoid Xreceptor agonist, in healthy volunteers.

Cilofexor is a nonsteroidal farnesoid X receptor (FXR) agonist being evaluated for treatment of nonalcoholic steatohepatitis (NASH) and primary sclerosing cholangitis (PSC). This work characterized the pharmacokinetics, pharmacodynamic, safety, and tolerability of cilofexor in healthy participants. Cilofexor single and multiple once-daily doses (10 to 300 mg fasting or fed and twice-daily doses [15 and 50 mg; fed]; tablet formulation) were evaluated. In each cohort, participants were randomized to active drug or placebo in a 4:1 ratio (planned n=15/cohort). Multiple dosing was for 14 days. Pharmacokinetic and pharmacodynamic samples were collected and safety and tolerability were assessed. Overall, 120 participants were enrolled in the study and 118 participants received at least one dose of study drug. Cilofexor pharmacokinetics followed bi-exponential disposition and its exposure increased in a less-than-dose-proportional manner over the 10 to 300 mg dose range, with no significant accumulation with repeated dosing. Moderate-fat meal reduced cilofexor area under the plasma concentration versus time curve (AUC) by 21% to 45%. Cilofexor increased plasma levels of fibroblast growth factor19 (FGF19) and reduced the serum bile acid intermediate 7α-hydroxy-4-cholesten-3-one (C4) and bile acids in an exposure-dependent manner. Cilofexor doses >30 mg appeared to achieve the plateau of intestinal FXR activation. Cilofexor was generally well tolerated; all treatment-emergent adverse events (TEAEs) were mild or moderate in severity, with headache being the most frequently observed TEAE. The pharmacokinetics pharmacodynamic safety, and tolerability results from this study supported further evaluations, and informed dose selection, of cilofexor in phase II studies in patients with NASH and PSC.

Efficacy of Curcumin in the Management of Oral Submucous Fibrosis - An Intervention Study

Background and Objective: Oral submucous fibrosis (OSMF), a chronic, inflammatory, and potentially malignant disorder of the oral cavity, has been linked to the chewing of arecanuts. Antioxidants and quitting habits ought to both be incorporated into OSMF therapeutic interventions regimens. Current study aimed to determine curcumin’s efficacy as an antioxidant in the management of OSMF. Materials and Methods: In this intervention study, 42 participants with OSMF were allocated into three groups. Group A received curcumin; group B received intralesional steroid injections; and group C received neither treatment (placebo group). For three months, groups A and B received twice-daily doses of 400 mg of curcumin each, while group C received twice-daily doses of placebo capsules. Group B also received biweekly intralesional steroid injections of 4 mg/ml of betamethasone. Data were analyzed using statistical tests. Results: After receiving interventions, group B patients showed clinically significant improvements in mouth opening. Both Group A and B reported a burning sensation reduction that was statistically significant. Statistically, greater improvement in mouth opening and a decrease in burning sensation were reported in group A. Conclusion: When employed as a combination therapy in the initial management of people with OSMF, curcumin can help patients with their clinical symptoms. Future research is recommended to use larger samples and longer treatment follow-up periods.

Comparative Study of OD (Tacrolimus Extended-Release Capsules) Versus Conventional Tacrolimus in Renal Transplant Patients

One of the common causes of chronic allograft nephropathy is non adherence to medications contributing to 30% of graft loss in developed world. The non-adherence is attributed to pill burden. Once-daily dosing of tacrolimus instead of conventional twice-daily dosing may enhance adherence to medication and improve long-term outcomes.

Phase 1 Study of the Selective c-MET Inhibitor, HS-10241, in Patients With Advanced Solid Tumors

Introductionc-MET is an important therapeutic target for various cancers; however, the People’s Republic of China currently retails only one specific c-MET inhibitor. Our preclinical study has revealed the high selectivity of HS-10241 to suppress c-MET. This phase 1 study aims to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of the selective c-MET inhibitor (HS-10241) in patients with advanced solid tumors. MethodsPatients with locally advanced or metastatic solid tumors orally received a single or multiple dose of HS-10241 once daily or twice daily for 21 consecutive days, which included the following six regimens: 100 mg once daily, 200 mg once daily, 400 mg once daily, 600 mg once daily, 200 mg twice daily, and 300 mg twice daily. The treatment continued until disease progression, unacceptable toxicity, or treatment termination. The primary end point was the incidence of dose-limiting toxicity and maximal tolerated dose (MTD). Secondary end points included safety, tolerability, pharmacokinetics, and pharmacodynamics. ResultsA total of 27 patients with advanced NSCLC received HS-10241, and dose-limiting toxicity was observed in three patients after 600 mg once-daily HS-10241 treatment. For once-daily dosing, MTD was 400 mg, and for twice-daily dosing, the maximal safe escalated dose was 300 mg, and MTD was not reached. Nausea (48.1%, 13 of 27), fatigue (37.0%, 10 of 27), and anemia (33.3%, 9 of 27) are the three most frequent treatment-emergent adverse events. At 400 mg once daily, Css,max was 5076 ng/mL and steady state area under the curve was 39,998 h × ng/mL. Patients (n = 5) with positive MET (MET exon 14-skipping, MET amplified, and MET immunohistochemistry 3+) had confirmed partial responses (n = 1) or stable disease (n = 3), with a disease control rate of 80.0%. ConclusionsThe selective c-MET inhibitor HS-10241 was well tolerated and had clinical activity in advanced NSCLC, especially in patients with positive MET. Furthermore, this study expounds on the therapeutic potential of HS-10241 in patients with cancer.

Comparative study of once daily tacrolimus (extended-release capsule) versus conventional twice daily tacrolimus in renal transplant recipients

Background: One of the common causes of chronic allograft nephropathy is nonadherence to medications, contributing to 30% of graft loss in the developed world. The non-adherence is attributed predominantly to pill burden. Once-daily dosing of tacrolimus instead of conventional twice-daily dosing may enhance adherence to medication and improve long-term outcomes. The present study is a retrospective analysis comparing the safety and effectiveness of De Novo (use from day 1) once daily (OD) Tacrolimus (extended-release capsules) to conventional twice-a-day (BD) tacrolimus, in renal transplant recipients operated at Suguna Hospital Bangalore India. Material and Methods: Records of 24 Transplant patients on De novo OD Tacrolimus were analyzed and compared retrospectively to 24 transplant patients treated De Novo with conventional BD tacrolimus on a regular follow-up for at least 2 yrs. post-transplant at our center. Results: Various parameters recorded till the last follow-up were analyzed and compared. The average weight of the cohort (64.6 kg vs. 66.6 kg), average tacrolimus dose (2.7 mg vs. 2.15 mg), average Tac dose/kg body weight (0.04 mg vs. 0.03 mg), average Sr.Creatinine, at Last, Follow up (1.2 mg/dl vs. 1.32 mg/dl) were comparable in both groups and were statistically insignificant (p &gt; 0.05). However, there was a higher incidence of Post-Transplant Diabetes Mellitus (PTDM) noted in the Conventional BD Tacrolimus group (20.83%) compared to the OD Tacrolimus group (4.1%) and it was statistically significant (p = 0.17). The Infection rate of 41.67% in the conventional BD Tacrolimus group was much higher compared to the OD Tacrolimus group (4.17%) which was statistically significant (p = 0.01). There was 100% patient and graft survival at the end of two years in both groups. Tacrolimus Dose for OD and Conventional BD dosing were similar, unlike earlier studies recommending a 10% increase in dose for OD tacrolimus compared to BD dosing. Conclusion: OD Tacrolimus dose is comparable to conventional BD dose Tacrolimus in its safety and Efficacy; however, it scores over conventional BD dose Tacrolimus in terms of post-transplant infections and post-transplant diabetes mellitus (PTDM) and a more stable serum trough level.

Characterization of Real-World Chronic Graft-Versus-Host-Disease Patients Receiving Belumosudil

Introduction Chronic graft-versus-host-disease (cGVHD) is a common complication of hematopoietic stem cell transplant (HSCT). cGVHD is characterized by inflammation and fibrosis that negatively impact multiple organ systems, resulting in substantial morbidity and mortality. While many systemic therapies are available to treat cGVHD, these therapies are associated with adverse events that may limit treatment adherence or lead to discontinuation. In July 2021, the Rho-associated coiled-coil kinase 2 (ROCK2) inhibitor belumosudil was approved by the United States Food and Drug Administration for the treatment of cGVHD for patients 12 years and older after failure of at least two prior lines of systemic therapy based on the efficacy observed in a randomized, open-label, multicenter trial (NCT03640481). Characteristics of patients being treated with belumosudil outside of a clinical trial have not been described previously. The objective of this study is to understand the real-world, non-clinical trial use of belumosudil for patients with cGVHD. Methods This retrospective study describes cGVHD patients recorded in the Komodo closed claims dataset between January 2016 and March 2022. The final cohort of interest included patients who were diagnosed with cGVHD (≥1 medical claim with the International Classifications of Disease Version 10 [ICD-10] diagnosis code D89.811), received belumosudil (≥1 claims with National Drug Code 79802020030), and were 12 years of age or older in the year of belumosudil initiation. Patients were required to have at least 36 months of continuous medical and pharmacy enrollment prior to their initial belumosudil prescription to ensure a complete medical diagnosis, treatment, and healthcare utilization history. Results A total of 151 patients were identified [median (interquartile range) age of 53 (40-62) years old; 54% female]. Sixty percent (92/151) of the patients had an HSCT within the 36-month observation period, and 73% (67/92) of the patients with an observable HSCT also had a diagnosis for a hematologic cancer in the 3 months prior to their HSCT. The median times from HSCT (in those with a recorded event) and cGVHD diagnoses (in all patients available) to belumosudil initiation were 3.2 (1.7-4.0) and 1.5 (0.5-3.1) years, respectively. During the 36 months pre-belumosudil treatment, common diagnoses included dyspnea (81%, 123/151), cytopenia (79%, 119/151; includes anemia, neutropenia, and thrombocytopenia), and "complications of stem cell transplant" (76%, 115/151; ICD-10 code T86.5). In the 12 months immediately prior to belumosudil initiation, the mean (standard deviation) Charlson Comorbidity Index score was 3.6 (2.2); a median of 9 (4-20) cGVHD-related healthcare encounters occurred; and nearly half of all patients had a hospitalization (all-cause 48%, 73/151; cGVHD-related, 27%, 41/151), with the most frequent primary diagnoses for admission attributed to respiratory illnesses and transplant complications. The majority of patients had received ≥3 lines of cGVHD treatment (85%, 128/151) in the 36 months pre-belumosudil, with a median of 5 (4-6) systemic therapies. Combination therapies containing either calcineurin inhibitors (17%; 25/151) or ruxolitinib (15% 23/151) were the most common lines of therapy immediately prior to belumosudil prescription. Use of strong Cytochrome P450 Family 3 Subfamily A (CYP3A) inducers was not observed during the observation period. In the 12 months prior to belumosudil initiation, 55% (83/151) patients were prescribed proton pump inhibitors. For the first belumosudil prescription that a patient received, 74% (111/151) of patients received once-daily dosing, and 26% (40/151) of patients received twice-daily dosing. Conclusions In this real-world data, prior to receiving belumosudil, patients received a median of 5 lines of systemic therapies at a median of 1.5 years from cGVHD diagnosis. Patients displayed multiple comorbidities and frequent hospitalizations that could complicate clinical management with existing cGVHD therapies. There is an unmet need for safe and effective treatment for cGVHD patients. Further research is needed to describe outcomes for patients being treated with belumosudil.

Differences in Durability of PARP Inhibition by Clinically Approved PARP Inhibitors: Implications for Combinations and Scheduling.

Six PARP inhibitors (PARPi) are approved for cancer therapy as monotherapy agents in daily or twice-daily continuous dosing schedules to maintain the necessary continuous suppression of PARP activity. Continuous PARP inhibition is required for single-agent anticancer activity. To investigate if such intense schedules are necessary, we determined the durability of PARP inhibition up to 72 h after a 1 h pulse of 1 µM of five of the approved PARPi, rucaparib, olaparib, niraparib, talazoparib and pamiparib, in IGROV-1 and ES-2 (human ovarian cancer) cells. Rucaparib caused the most persistent inhibition of PARP activity when maintained at ≥75% at 72 h after drug withdrawal in both IGROV-1 and ES-2 cells, but inhibition was more rapidly lost with the other PARPi. PARPi are also under clinical investigation with ATR inhibitors, and thus, we evaluated the implications for scheduling with an ATR inhibitor (VE-821). Rucaparib enhanced VE-821 cytotoxicity in co-exposure, sequential and delayed (24 h drug-free) schedules in IGROV-1 and ES-2 cells. Olaparib and niraparib enhanced VE-821 cytotoxicity only in co-exposed cells and not in sequential exposures. These data have clinical implications for the scheduling of PARPi as a monotherapy and in combination with ATR inhibitors and other cytotoxic drugs.

Personalized allocation of acetylsalicylic acid therapy for secondary prevention of coronary artery disease.

BackgroundA single-daily dose of 75 mg of acetylsalicylic acid inhibits 100% of thromboxane-B2 synthesis within 30–60 min. Thromboxane-B2 synthesis then recovers slowly as new platelets are released from the bone marrow. Normally, only 10% of the platelets are replaced daily by new platelets entering circulation. Hence, 24 h after a dose of acetylsalicylic acid, thromboxane-B2 synthesis is still suppressed by more than 90%. Hence, there is an adequate anti-platelet effect even after 24 h of acetylsalicylic acid intake. However, some patients treated with once-daily acetylsalicylic acid may have an incomplete 24-h suppression of thromboxane-B2 synthesis due to increased platelet turnover. The response could be improved in such patients by twice-daily acetylsalicylic acid administration. This study aimed to identify such a group of patients who would benefit from a twice-daily dose of acetylsalicylic acid.Materials and methodsSerum thromboxane-B2 levels were measured in 79 patients with coronary artery disease receiving 75 mg of acetylsalicylic acid for secondary prophylaxis. Serum levels of thromboxane-B2 were measured after 4 and 24 h of acetylsalicylic acid intake. Patients were then classified into three groups: steady suppression group (serum thromboxane B2 is adequately suppressed at 4 and 24 h), i.e., adequate response to acetylsalicylic acid; fast recovery group (more than 10% rise in serum thromboxane-B2 levels at 24-h when compared to at 4-h) and non-responders (serum thromboxane-B2 levels of >3,100 pg/ml after 4 h of acetylsalicylic acid intake). Patients in the fast recovery group were given twice-daily acetylsalicylic acid and thromboxane-B2 levels were re-measured.ResultsA total of 20 patients (24.3%) had steady suppression of thromboxane-B2 and 11 patients (13.9%) belonged to the fast recovery group, i.e., thromboxane-B2 levels were adequately suppressed at 4 h but had recovered by more than 10% at 24 h; which was adequately suppressed by twice-daily acetylsalicylic acid (p 0.004). A total of 48 patients (60.8%) were non-responders.ConclusionTwice-daily acetylsalicylic acid may be beneficial if serum thromboxane-B2 levels at 4 h are <3,100 and >3,100 pg/ml at 24 h. If thromboxane-B2 levels at 4 and 24 h is <3100 pg/ml but if there is a >10% rise in serum thromboxane B2 at 24 h as compared to that at 4 h, then twice-daily acetylsalicylic acid should be considered. However, if thromboxane-B2 at 4 and 24 h is >3,100 pg/ml consider switching over to a P2Y12 inhibitor.

Dermoscopic evaluation of the efficacy of combination of topical spironolactone 5% and minoxidil 5% solutions in the treatment of androgenetic alopecia: A cross sectional-comparative study.

Androgenetic alopecia (AGA) is a common chronic dermatological illness that affects both men and women. To assess and compare dermoscopically the impact of a combination of topical minoxidil solution (5%) and topical spironolactone solution (5%) in treating AGA in both sexes. One hundred and twenty patients diagnosed with AGA were divided into three groups; each group is composed of 40 patients. Group A (n=40) were treated with a 5% topical minoxidil solution, group B (n=40) were treated with a 5% topical spironolactone solution, and group C (n=40) were treated with a 5% topical minoxidil and spironolactone combination. Following the initiation of treatment and at 6 weeks (midterm), reduction in all dermoscopic features was observed in all groups; however, it was not statistically significant except for vellus hair reduction (p=0.033). On the contrary, upright regrowing hairs were insignificantly increased in all groups (p=1.088). The pattern of dermoscopic features remained to insignificantly decrease toward the end of 12 weeks treatment (full term) in all studied groups except for vellus hair that showed further significant reduction toward the end of the study (p=0.011). Both spironolactone as a 5% topical solution and minoxidil as a 5% topical solution might be used safely in a twice-daily dosage to treat AGA in both genders. Furthermore, combining them in a single topical dose form can boost efficacy and yield greater advantages.

Clinical Pharmacokinetics and Pharmacodynamics of Rucaparib.

Rucaparib is an oral small-molecule poly(ADP-ribose) polymerase inhibitor indicated for patients with recurrent ovarian cancer in the maintenance and treatment settings and for patients with metastatic castration-resistant prostate cancer associated with a deleterious BRCA1 or BRCA2 mutation. Rucaparib has a manageable safety profile; the most common adverse events reported were fatigue and nausea in both indications. Accumulation in plasma exposure occurred after repeated administration of the approved 600-mg twice-daily dosage. Steady state was achieved after continuous twice-daily dosing for a week. Rucaparib has moderate oral bioavailability and can be dosed with or without food. Although a high-fat meal weakly increased maximum concentration and area under the curve, the effect was not clinically significant. A mass balance analysis indicated almost a complete dose recovery of rucaparib over 12 days, with metabolism, renal, and hepatic excretion as the elimination routes. A population pharmacokinetic analysis of rucaparib revealed no effect of age, sex, race, or body weight. No starting dose adjustments were necessary for patients with mild-to-moderate hepatic or renal impairment; the effect of severe organ impairment on rucaparib exposure has not been evaluated. In patients, rucaparib moderately inhibited cytochrome P450 (CYP) 1A2 and weakly inhibited CYP3As, CYP2C9, and CYP2C19. Rucaparib weakly increased systemic exposures of oral contraceptives and oral rosuvastatin and marginally increased the exposure of oral digoxin (a P-glycoprotein substrate). In vitro studies suggested that rucaparib inhibits transporters MATE1, MATE2-K, OCT1, and OCT2. No clinically meaningful drug interactions with rucaparib as a perpetrator were observed. An exposure-response analysis revealed dose-dependent changes in selected clinical efficacy and safety endpoints. Overall, this article provides a comprehensive review of the clinical pharmacokinetics, pharmacodynamics, drug-drug interactions, effects of intrinsic and extrinsic factors, and exposure-response relationships of rucaparib.

Patient perspectives on dry eye disease and chronic ocular surface pain: Insights from a virtual community-moderated dialogue.

To understand patients' perspectives on living with dry eye disease (DED), and on the unmet needs in DED and chronic ocular surface pain (COSP) management. A moderated, structured discussion with patients with ocular surface diseases and healthcare professionals (HCPs) was conducted using a virtual platform to capture patients' journey with DED, their opinion on unmet needs, and design and conduct of clinical trials in DED and COSP. Nine participants, including four patient representatives from patient organisations, one ophthalmologist and one optometrist participated in the discussion. Patients had DED of varying severity and aetiology; three patients had Sjögren's. Over 4 weeks, 785 posts were entered on the platform. Prior to diagnosis, patients rarely associated their symptoms with DED. Convenience and symptomatic relief scored higher than treating the disease. Patients expressed the need for plain language information and dialogue with knowledgeable and sensitive HCPs. Online forums and social media were suggested as key recruitment resources, whereas convenience and safety concerns were highlighted as main barriers to enrolment. The need for the inclusion of outcome measures that have a real impact on patients' experience of their condition was highlighted. Both target product profiles were received positively by participants, highlighting the twice-daily dosing regimen and convenience of the products. Participants acknowledged the value of digital tools and suggested the need to feel valued post-trial. This moderated dialogue provided actionable insights on the unmet needs in DED and useful inputs for consideration when designing future clinical trials for DED and COSP.

To deprescribe or not to deprescribe, that is the question

To deprescribe or not to deprescribe, that is the question

1397P Phase I results of exicorilant plus enzalutamide in patients with castration-resistant prostate cancer

Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease with significant morbidity, despite the availability of multiple classes of therapies. Combining the selective glucocorticoid receptor (GR) modulator exicorilant (EXI) with the androgen receptor (AR) antagonist enzalutamide (ENZA) may block an important tumor escape pathway via dual antagonism of GR and AR. We report safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) results from the first study evaluating EXI + ENZA in patients with CRPC. Segment 1 of this phase 1/2a dose-finding study (NCT03437941) evaluated open-label, twice-daily dosing of EXI. Patients (irrespective of prior ENZA exposure) received either EXI 180 mg BID + ENZA 160 mg QD, EXI 140 mg BID + ENZA 160 mg QD with a 28-day ENZA lead-in, or EXI 140 mg BID + ENZA 160 mg QD without an ENZA lead-in. Segment 2 evaluated QD dosing of EXI in a double-blind design in patients on a stable ENZA dose with rising PSA (25% increase over nadir and absolute value >1 ng/mL). All patients received EXI 240 mg QD + ENZA and were randomized 3:1 to EXI titration (to 280 mg followed by 320 mg) or to stay on EXI 240 mg. PK (EXI, ENZA) and PD (including cortisol and ACTH) were measured throughout the study. 14 and 25 patients were enrolled in segments 1 and 2, respectively. 37 patients received at least one dose of EXI. Most frequent EXI-related adverse events (AEs) included fatigue (57%), back pain (35%), decreased appetite (27%), and neuropathic pain (22%). Dose-limiting toxicities were fatigue, musculoskeletal pain, and pancreatitis in segment 1, and fatigue, lipase increase, hypophosphatemia, AST/ALT/GGT increase, back pain, and vomiting in segment 2. EXI exposures were largely overlapping across dose levels in segment 2. No clinically relevant changes in the exposures of ENZA or its active metabolite, N-desmethyl ENZA, were observed when combined with EXI. ENZA exposures were consistent with historical data for ENZA 160 mg alone. A maximum-tolerated dose of EXI in combination with ENZA was identified with fatigue and pain as the most common AEs. No clinically relevant changes were observed in ENZA exposure when given with EXI relative to ENZA alone.

Clinical Observations Associated with Phenobarbital Serum Monitoring to Manage Epilepsy in a California Sea Lion with Domoic Acid Toxicosis

The marine algal toxin domoic acid is an important threat to marine mammal health, and exposure can lead to both acute neurologic signs and a chronic epileptic syndrome in California sea lions (Zalophus californianus). Phenobarbital has been used for several decades to manage seizures, although reports are limited correlating dosing, serum monitoring and clinical efficacy in this species. This report details serum monitoring over 33 months in an 8-year-old male sea lion. Seizure control was achieved when phenobarbital concentrations were above 18 μg/mL, and sedation and ataxia were noted when concentrations were above 35 μg/mL. There was no clinically significant difference between phenobarbital concentrations resulting from once-daily versus twice-daily dosing. Serum levels remained detectable as far as 101 days after administration, and remained stable during periods of prolonged anorexia, although dramatic decreases in serum concentrations were noted immediately after normal eating resumed. For this animal, a serum phenobarbital target range of 20–30 μg/mL was achievable with a dose of 1.5 mg/kg once daily followed by therapeutic monitoring, and this is a reasonable recommended concentration and initial dose for clinicians treating this species. Long-term seizure control may be difficult to achieve with anti-epileptic drugs such as phenobarbital alone, and further research is needed to make novel options useful for clinical management of biotoxin-related neurologic disease in this aquatic species.

Dolutegravir for children with HIV-associated tuberculosis

In The Lancet HIV, Anna Turkova and colleagues1 report the findings of a pharmacokinetic and safety substudy nested within the ODYSSEY trial, which provides evidence that twice-daily dolutegravir dosing is safe and effective when used with rifampicin-containing tuberculosis (TB) treatment in children with HIV-associated TB. Their findings support the 2021 WHO HIV recommendations for once-daily dolutegravir as a component of first-line and second-line HIV treatment from age 4 weeks or older, and twice-daily dosing during treatment with rifampicin-based therapy for TB coinfection.

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0-24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014-002632-14), and the ISRCTN registry (ISRCTN91737921). Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4-17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08-2·11) for Ctrough, 1·23 (0·99-1·53) for AUC0-24 h, and 0·94 (0·76-1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30-40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB. Penta Foundation, ViiV Healthcare, UK Medical Research Council.

Comparison of Viral Load Suppression among HIV-1 Infected Children Aged 5 to 12 Years on Once Daily Versus Twice Daily Abacavir-Containing Regimens at University Teaching Hospitals - Children’s Hospital, Lusaka, Zambia

Abacavir is one of the first-line drugs used to treat HIV infection in paediatric patients in Zambia, whose use in children has not been widely published. This study compared the virologic response of abacavir given as part of a once-daily regimen with the response when given as part of a twice-daily regimen. A total of eighty-two children aged two to twelve years currently receiving antiretroviral therapy at the Paediatric Centre of Excellence, University Teaching Hospitals, Lusaka, Zambia, were observed in the study. This was a prospective cohort study. All the children were initially on twice daily abacavir containing regimen with lamivudine twice daily and efavirenz once daily, with 40 maintained on this regimen by the attending clinician and 42 switched to once-daily abacavir, lamivudine and efavirenz by the attending clinician. Profiles were obtained for each child to compare viral load at baseline and week 24. Data was analysed using Stata Version 16.The proportion of children with undetectable viral load in the once-daily group at twenty-four weeks was 64.3 per cent compared to 72.5 per centin the twice-daily group. Twice-daily dosing reduced the odds of achieving an undetectable viral load by about 59 per cent, while being male reduced the odds of achieving an undetectable HIV viral load by 19.6 per cent. Baseline haemoglobin, creatinine, or alanine transferase levels were not predictors of viral load suppression.The study suggests that once-daily dosing of an abacavir-containing regimen achieved a lower viral suppression rate when compared to twice-daily dosing. It is recommended that once-daily dosing of abacavir containing regimen should be considered as a dosing option for Zambian children living with HIV.

Pediatric AIDS-Therapeutic Successes Built on a Foundation of Pediatric Clinical Pharmacology with Pharmacokinetic-Pharmacodynamic Modeling.

Pediatric AIDS-Therapeutic Successes Built on a Foundation of Pediatric Clinical Pharmacology with Pharmacokinetic-Pharmacodynamic Modeling.