Application of Exposure-Response Analyses to Establish the Pharmacodynamic Similarity of a Once-Daily Regimen to an Approved Twice-Daily Dosing Regimen for the Treatment of HCV Infection

ABSTRACT In an in vitro pharmacodynamic model, a twice-daily cefdinir dosing regimen was more effective than a once-daily regimen against common bacterial respiratory pathogens in producing 3-log10killing and preventing the occurrence of regrowth at 24 h. Twice-daily administration is likely the more appropriate cefdinir dosing strategy for the treatment of community-acquired pneumonia.

Download Full-text

Exposure-Response of Quizartinib Efficacy in Patients with Relapsed/Refractory AML

Blood ◽

10.1182/blood-2019-122582 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1263-1263

Author(s):

Dongwoo Kang ◽

Julie Passarell ◽

Malaz A Abutarif ◽

Jeanne Mendell ◽

Ophelia Yin

Keyword(s):

Complete Remission ◽

Phase 2 ◽

Dosing Regimen ◽

Phase 3 ◽

Once Daily ◽

Exposure Response ◽

Phase 2 Study ◽

Quartile Group ◽

Cyp3a Inhibitor ◽

To Receive

Introduction: Quizartinib is a once-daily, oral, highly potent and selective FLT3 inhibitor that has shown clinical activity in patients with relapsed/refractory acute myeloid leukemia (AML) with FLT3 internal tandem duplications in the phase 3 QuANTUM-R trial (Cortes et al, Lancet Oncol 2019; NCT02039726). In this analysis, exposure-response relationships of select efficacy endpoints of quizartinib were evaluated. Methods: Analysis was conducted for the following 2 studies separately: phase 2 study APS2689-CL-2004 and phase 3 QuANTUM-R study. Phase 2 study APS2689-CL-2004 enrolled 76 patients who were randomized to receive quizartinib 30 or 60 mg once daily (26.5 and 53.0 mg free base, respectively). Dose escalation was allowed and no dose reduction for strong cytochrome P450 3A (CYP3A) inhibitors was made in this study. In QuANTUM-R, 245 patients were randomized to receive quizartinib. The quizartinib dosing regimen was 30 mg/day and then escalated to 60 mg/day after 2 weeks if QTcF was ≤ 450 ms. Patients receiving a concurrent strong CYP3A inhibitor initiated quizartinib at 20 mg/day, with an increase to 30 mg/day, because concomitant use of a strong CYP3A inhibitor approximately doubles quizartinib exposure. Efficacy endpoints included in the analysis were rate of composite complete remission (CRc; complete remission (CR) + complete remission with incomplete platelet recovery + complete remission with incomplete hematologic recovery), duration of CRc, and overall survival (OS). Exposure measures in individual patients, such as average daily area under the curve (AUC), maximum concentration, and trough concentration, were obtained from a population pharmacokinetic analysis of quizartinib plasma concentration data (Kang et al, EHA 2019) and then used for correlating with the efficacy endpoints. Logistic regression analysis was used for CRc rate, and time-to-event analysis was performed for the duration of CRc and OS. The effect of quizartinib exposure on the percentage of subjects achieving bone marrow (aspirate) blasts of < 5% in QuANTUM-R was also assessed. Results: Patients were divided into 4 quartile groups according to average daily quizartinib AUC for the investigation of exposure-response relationships for OS and the duration of CRc. The lowest exposure quartile group showed shorter OS than the higher 3 quartile groups. The overall median OS from the intent-to-treat (ITT) population was 6.2 months in the phase 3 study; the median OS in the lowest exposure quartile group (Q1) was 4.5 months, whereas the median OS in the highest exposure quartile group (Q4) was 9.6 months (Fig. 1). Analysis of OS for the phase 2b study APS2689-CL-2004 demonstrated a similar trend, in which the lower AUC quartile demonstrated decreased OS. The overall OS from the ITT population was 5.2 months in the phase 2 study, and the median OS in Q1 and Q4 was 4.6 and 6.9 months, respectively (Fig. 2). Consistent with analyses for OS, the duration of CRc showed a trend of shorter duration of response in the lower AUC quartiles in both studies. Additionally, the lower AUC quartile appeared to result in a smaller proportion of subjects who achieved blast reduction of < 5% (ie, 33.3% in Q1 vs 45.6% to 52.6% in Q2 to Q4). However, no apparent trend of exposure-response relationship was shown for CRc (P > .05 from logistic regression analysis). Conclusions: Exposure-response analysis suggests a consistent trend for reduced clinical benefit at lower quizartinib AUC quartiles across various efficacy endpoints (but not CRc) in both the phase 2 and phase 3 studies. Current analysis supports the recommended dosing regimen of 30-mg starting dose with escalation to 60 mg as the target clinical dose. Figure Disclosures Kang: Daiichi Sankyo: Employment. Passarell:Cognigen Corporation: Employment. Abutarif:Daiichi Sankyo: Employment, Equity Ownership. Mendell:Daiichi Sankyo, Inc.: Employment. Yin:Daiichi Sankyo: Employment.

Download Full-text

Evaluation of Low-Dose Gentamicin Once Daily Dosing Regimen at A General Hospital in Malaysia

International Journal of Pharmaceutical Quality Assurance ◽

10.25258/ijpqa.v9i01.11351 ◽

2018 ◽

Vol 9 (01) ◽

Author(s):

Ab Rahman A F ◽

Md Sahak N. ◽

Ali A. M.

Keyword(s):

Medical Records ◽

Public Hospital ◽

Low Dose ◽

Dosing Regimen ◽

Once Daily ◽

Neutropenic Sepsis ◽

Wide Acceptance ◽

The Mean ◽

Initiation Of Therapy ◽

Almost All

Objective: Once daily dosing (ODD) aminoglycoside is gaining wide acceptance as an alternative way of dosing. In our setting it is the regimen of choice whenever gentamicin is indicated. The objective of this study was to evaluate the practice of gentamicin ODD in a public hospital in Malaysia. Methods: We conducted a retrospective review of medical records of patients on gentamicin ODD who were admitted to Hospital Melaka during January 2002 until March 2010. All adult patients who were on ODD gentamicin with various level of renal function were included in the study. Patients on gentamicin less than 72 hours and pregnant women were excluded. Results: From 110 patients, 75 (68.2%) were male and 35 (31.8%) were female. Indications for ODD gentamicin included pneumonia, 34 (31.0%) neutropenic sepsis, 27 (24.5%) and sepsis, 11 (10.0%). The mean dose and duration of gentamicin was 3.2 mg/kg/day and 7 days, respectively. Almost all patients were on gentamicin combined with other antibiotics. Clinical cure based on fever resolution was found in 89.1% of patients treated with ODD. Resolution of fever took an average of 48 hours after initiation of therapy. The evaluation for bacteriologic cure could not be performed because of insufficient data on culture and sensitivity. Out of 38 patients with analyzable serum creatinine data, four patients might have developed nephrotoxicity. Conclusion: In our setting, lower dosages of ODD gentamicin when used in combination with other antibiotics seemed to be effective and safe in treating most gram negative infections.

Download Full-text

Comparison of a once Daily with a twice Daily Subcutaneous Low Molecular Weight Heparin Regimen in the Treatment of Deep Vein Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615089 ◽

1998 ◽

Vol 79 (05) ◽

pp. 897-901 ◽

Cited By ~ 52

Author(s):

Bernard A. Charbonnier ◽

Jean-Noël Fiessinger ◽

J. D. Banga ◽

Ernst Wenzel ◽

Pascal d’Azemar ◽

...

Keyword(s):

Molecular Weight ◽

Pulmonary Embolism ◽

Deep Vein Thrombosis ◽

Low Molecular Weight Heparin ◽

Low Molecular Weight ◽

Daily Regimen ◽

Once Daily ◽

Daily Group ◽

Vein Thrombosis ◽

Deep Vein

SummaryBackground: Clinical trials have been performed to compare with standard heparin a once or a twice daily regimen of low-molecular-weight heparin but no direct comparison has been done between these two low-molecular-weight heparin regimens in terms of efficacy and safety with a long-term clinical evaluation.Methods: Patients with proximal deep vein thrombosis, confirmed by venography were randomly assigned to either nadroparin (10,250 AXa IU/ml) twice daily or nadroparin (20,500 AXa IU/ml) once daily for at least 5 days. Regimens were adjusted to bodyweight. Oral anticoagulants were started on day 1 or 2 and continued for 3 months. Patients were followed up for 3 months. The composite outcome of venous thromboembolism and death possibly related to pulmonary embolism was the primary measure of efficacy. Major bleeding was the principal measure of safety. The study was designed to show equivalence between the two regimens.Results: Recurrent thromboembolic events or death possibly related to pulmonary embolism were reported in 13 patients in the once daily group (4.1%) and in 24 patients of the twice daily group (7.2%): (absolute difference 3.1% in favor of the once daily regimen; 95% confidence interval -6.6%, +0.5%). Major bleeding episodes during nadroparin treatment occurred in 4 (1.3%) and 4 patients (1.2%) in the once and twice daily groups, respectively.Conclusions: A nadroparin regimen of one injection per day is at least as effective and safe as the same total daily dose divided over two injections for the treatment of acute deep vein thrombosis.

Download Full-text

SAT0149 EXPOSURE-RESPONSE RELATIONSHIPS FOR EFFICACY AND SAFETY OF FILGOTINIB AND ITS METABOLITE GS-829845 IN SUBJECTS WITH RHEUMATOID ARTHRITIS BASED ON PHASE 2 AND PHASE 3 STUDIES

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4977 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1013-1014

Author(s):

A. Meng ◽

K. Anderson ◽

C. Nelson ◽

B. Kirby ◽

L. Ni ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Response Rates ◽

High Response ◽

Phase 2 ◽

Phase 3 ◽

Once Daily ◽

Exposure Response ◽

Serious Infections ◽

Wide Range ◽

Grade 3

Background:Filgotinib is an orally administered small molecule that provides selective inhibition of JAK1, a signaling molecule that helps drive inflammatory pathways underlying rheumatoid arthritis (RA).Objectives:Exposure-response (ER) analyses were performed for efficacy following completion of Phase 2 studies over a wide range of doses to support evaluation of 200mg and 100 mg once daily in Phase 3 studies. ER analyses were subsequently performed by using Phase 3 efficacy data to support selection of the proposed registrational dose. ER analyses for safety based on pooled Phase 2 and Phase 3 studies were conducted to examine the safety of evaluated doses.Methods:Population PK analyses were conducted to estimate plasma exposures of filgotinib and GS-829845 (major circulating active metabolite of filgotinib) in both Phase 2 (DARWIN 1 and DARWIN 2) and Phase 3 studies (FINCH 1, FINCH 2, and FINCH 3) encompassing a dose range of 25 to 100 mg twice daily and 50 to 200 mg once daily. As both filgotinib and GS-829845 contribute to efficacy via JAK1 inhibition, their exposures were combined into single parameters, AUCeff and Ctau-eff (effective area under the curve and effective concentration at trough, by accounting for relative inhibition potency and molecular weight) in the ER analyses for various efficacy endpoints (e.g ACR20/50/70 responses) at Week 12 and Week 24. The ER analyses for safety endpoints (the 5 most frequent treatment-emergent adverse events [TEAEs] and Grade 3 or 4 laboratory abnormalities, serious TEAEs, and serious infections) were performed separately for filgotinib and GS-829845 exposures to characterize the individual safety profile of each analyte. The 5 evaluated TEAEs were nausea, nasopharyngitis, upper respiratory tract infection, headache, and hypertension; the 5 Grade 3/4 laboratory abnormalities included lymphocytes decrease, glucose increase, phosphate decrease, triacylglycerol lipase increase, and creatine kinase increase.Results:In the ER analyses for efficacy based on Phase 2 studies, high response rates were demonstrated in ACR20/50/70 across all octile groups in subjects with RA receiving filgotinib and the ER supported further evaluation of both 200 mg and 100 mg once daily doses in Phase 3 clinical studies. Similarly, ER relationships based on pooled Phase 3 studies across various endpoints (e.g ACR20/50/70) consistently revealed high response rates across the exposure range for both the filgotinib 200 mg and 100 mg doses. A trend of increasing response with increasing exposure was observed over the exposure range for multiple secondary efficacy endpoints including ACR50 and ACR70 with the effective exposures at filgotinib 200 mg primarily residing on the plateau of the ER curves.Filgotinib was generally well-tolerated with no individual TEAE or Grade 3 or 4 laboratory abnormality > 5% in the filgotinib 200 mg once daily group up to Week 12. No relationships were observed between filgotinib and GS-829845 exposures (AUC0-24 and Cmax) and the most frequent TEAEs, Grade 3/4 laboratory abnormalities, serious TEAEs, or serious infections up to Week 52.Conclusion:ER analyses demonstrate that both the 200 mg and 100 mg once daily filgotinib doses are efficacious in subjects with moderately to severely active RA without clear dose-dependent effects on safety. The trend towards greater efficacy with higher exposures for some secondary endpoints (ACR50 and ACR70) and a lack of exposure-safety relationship supports a dose of 200 mg once daily over 100 mg once daily since it presents the best benefit/risk ratio among the doses tested.Disclosure of Interests: :Amy Meng Shareholder of: Gilead Sciences, Employee of: Gilead, Kacey Anderson Shareholder of: Gilead Sciences, Employee of: Sciences, Cara Nelson Shareholder of: Gilead, Employee of: Gilead, Brian Kirby Shareholder of: Gilead, Employee of: Gilead, Liyun Ni Shareholder of: Gilead, Employee of: Gilead, Shu-Min Chuang Shareholder of: Gilead, Employee of: Gilead, Brian Kearney Shareholder of: Gilead, Employee of: Gilead, Anita Mathias Shareholder of: Gilead, Employee of: Gilead

Download Full-text

Extended Experience in the Use of Antibiotic Lock for Eradication of Biofilm Bacteria on Tenckhoff Catheter

Peritoneal Dialysis International ◽

10.3747/pdi.2018.00098 ◽

2019 ◽

Vol 39 (2) ◽

pp. 187-190 ◽

Cited By ~ 1

Author(s):

Steve S. Wong ◽

Wai-Yan Lau ◽

Ping-Kwan Chan ◽

Ching-Kit Wan ◽

Yuk-Lun Cheng

Keyword(s):

Equivalent Amount ◽

Daily Regimen ◽

Once Daily ◽

Tenckhoff Catheter ◽

Long Period ◽

Lock Solution ◽

Catheter Lock ◽

Biofilm Bacteria ◽

Antibiotic Lock ◽

Lock In

Whilst antibiotic lock is effective to eradicate biofilm bacteria on hemodialysis catheters, this adjunctive method has scarcely been tested in peritoneal dialysis (PD) patients. After our previous successful experience of its use to salvage two Tenckhoff catheters, we encountered another patient with problematic biofilm-associated PD peritonitis who strongly refused catheter removal. As a result, antibiotic lock was given once daily, initially, with continuation of the usual PD schedule. However, relapsing peritonitis could not be prevented until we administered antibiotic lock without dialysate in the abdomen, which led to successful eradication of biofilm bacteria. To investigate the significance of having “dry abdomen” during antibiotic lock treatment, we injected an equivalent amount of contrast into the Tenckhoff catheter under fluoroscopy. We observed that the catheter lock solution could be retained over a long period of time only with “dry abdomen,” whereas rapid dissipation of the lock solution occurred in the presence of dialysate. We concluded that whilst antibiotic lock in a once-daily regimen can be highly effective against biofilm bacteria on a Tenckhoff catheter, it is essential to withhold PD exchanges during the dwell of antibiotic lock to prevent it from dissolving into the surrounding dialysate.

Download Full-text

A Randomized, Controlled Study of a Simple, Once-Daily Regimen of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated, Multidrug-Resistant Falciparum Malaria

Clinical Infectious Diseases ◽

10.1086/432011 ◽

2005 ◽

Vol 41 (4) ◽

pp. 425-432 ◽

Cited By ~ 88

Author(s):

E. A. Ashley ◽

R. McGready ◽

R. Hutagalung ◽

L. Phaiphun ◽

T. Slight ◽

...

Keyword(s):

Falciparum Malaria ◽

Multidrug Resistant ◽

Randomized Controlled Study ◽

Controlled Study ◽

Daily Regimen ◽

Once Daily ◽

Randomized Controlled

Download Full-text

Compliance as a Factor in the Development of Nitrate Tolerance: A Patient Investigation

Journal of International Medical Research ◽

10.1177/030006059302100106 ◽

1993 ◽

Vol 21 (1) ◽

pp. 51-57 ◽

Cited By ~ 2

Author(s):

P Löfdahl

Keyword(s):

Angina Pectoris ◽

Nitrate Concentration ◽

Nitrate Tolerance ◽

Isosorbide Mononitrate ◽

Dosing Regimen ◽

Once Daily ◽

Telephone Interviews ◽

The Times ◽

Plasma Nitrate ◽

Long Acting

Telephone interviews were conducted to establish the prescribing instructions given by experienced physicians to patients with angina pectoris treated with long-acting nitrates. In addition, the times of day when doses were taken were recorded. The aim of the study was to determine whether or not an asymmetric dosing regimen was being followed by the patients. The majority (62.7%) of patients were being treated with 5-isosorbide mononitrate taken orally twice daily. All but two took the correct number of tablets, but more than 50% of these patients were not taking the second tablet at the correct time to achieve the recommended 6 − 8-h period during which the plasma nitrate concentration was sufficiently low to avoid nitrate tolerance. Possible explanations for the incorrect use of the prescribed drug may be that the patients did not understand the physician's instructions and did not appreciate the importance of rigidly adhering to these instructions. A more satisfactory approach, with improved patient compliance, may be a once-daily dosing regimen.

Download Full-text

Population Pharmacokinetics of Doravirine and Exposure-Response Analysis in Individuals with HIV-1

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02502-18 ◽

2019 ◽

Vol 63 (4) ◽

Cited By ~ 8

Author(s):

Ka Lai Yee ◽

Aziz Ouerdani ◽

Anetta Claussen ◽

Rik de Greef ◽

Larissa Wenning

Keyword(s):

Virologic Failure ◽

Phase 1 ◽

Fixed Dose ◽

Response Analysis ◽

Population Pharmacokinetic ◽

Phase 3 ◽

Once Daily ◽

Intrinsic Factors ◽

Exposure Response ◽

Hiv 1

ABSTRACT Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV-1) infection. A population pharmacokinetic (PK) model was developed for doravirine using pooled data from densely sampled phase 1 trials and from sparsely sampled phase 2b and phase 3 trials evaluating doravirine administered orally as a single entity or as part of a fixed-dose combination of doravirine-lamivudine-tenofovir disoproxil fumarate. A one-compartment model with linear clearance from the central compartment adequately described the clinical PK of doravirine. While weight, age, and healthy versus HIV-1 status were identified as statistically significant covariates affecting doravirine PK, the magnitude of their effects was not clinically meaningful. Other intrinsic factors (gender, body mass index, race, ethnicity, and renal function) did not have statistically significant or clinically meaningful effects on doravirine PK. Individual exposure estimates for individuals in the phase 2b and 3 trials obtained from the final model were used for subsequent exposure-response analyses for virologic response (proportion of individuals achieving <50 copies/ml) and virologic failure. The exposure-response relationships between these efficacy endpoints and doravirine PK were generally flat over the range of exposures achieved for the 100 mg once-daily regimen in the phase 3 trials, with a minimal decrease in efficacy in individuals in the lowest 10th percentile of steady-state doravirine concentration at 24 h values. These findings support 100 mg once daily as the selected dose of doravirine, with no dose adjustment warranted for the studied intrinsic factors.

Download Full-text