Population pharmacokinetic modeling and simulations of dopamine Dd2 receptor occupancy of long-acting intramuscular risperidone-ISM

2016 ◽  
Vol 33 (S1) ◽  
pp. S572-S572
Author(s):  
J. Llaudó ◽  
L. Anta ◽  
I. Ayani ◽  
J. Martínez-González ◽  
I. Gutierro ◽  
...  
Keyword(s):  
Steady State ◽  
Dopamine D2 Receptor ◽  
Plasma Concentrations ◽  
Phase Iii ◽  
Population Pharmacokinetic ◽  
Two Phase ◽  
Phase Iii Trial ◽  
Population Pharmacokinetic Modeling ◽  
Population Pk ◽  
Long Acting

IntroductionRisperidone-ISM is a new long-acting intramuscular formulation intended to achieve sustained plasma concentrations over 4 weeks without oral supplementation. The clinical efficacy to risperidone has been associated with 65–80% occupancy of dopamine D2 receptor (D2RO) and a mean Cmax between 7.5 ng/mL and 80 ng/mL.AimUse a population PK/PD model to predict the PK and the D2RO for Risperidone-ISM in schizophrenic patients and to characterize the relationship among doses, in order to guide dose selection for a future Phase-III trial.MethodsA population PK/PD analysis for Risperidone-ISM using Monolix software was conducted based on 6641 plasma samples from two Phase-I studies (17 healthy subjects and 31 schizophrenic subjects, respectively) and 1 Phase-II study (60 schizophrenic subjects). Simulations were subsequently undertaken predicting the steady state PK and D2RO after multiple Risperidone-ISM doses administered every 28 days for 12 weeks.ResultsDoses of 75 and 100 mg, administered either in gluteal or deltoid muscle, were predicted to result in median Cmax and Ctrough that stayed between 7.5 ng/mL and 80 ng/mL. At steady state 75 mg and 100 mg dose (gluteal) achieved a D2RO average [min–max] of 70.8% [61.4–80.4] and 74.3% [66.2–82.1], respectively; a 75-mg and 100-mg dose (deltoid) achieved a D2RO average [min–max] of 69.3% [56.5–80.3] and 73.0% [61.8–82.1], respectively. The model estimated that the 65% D2RO occurs within first 8 h after treatment.ConclusionsSimulations were carried out supporting doses of 75 mg and 100 mg Risperidone-ISM to show the greatest efficacy and safety potential to be assessed in the future Phase-III trial.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Population pharmacokinetics of the rilpivirine long-acting formulation after intramuscular dosing in healthy subjects and people living with HIV

2021 ◽  
Author(s):  
M Neyens ◽  
H M Crauwels ◽  
J J Perez-Ruixo ◽  
S Rossenu
Keyword(s):  
Population Pharmacokinetics ◽  
Healthy Subjects ◽  
Phase Iii ◽  
Intramuscular Administration ◽  
Population Pharmacokinetic ◽  
People Living With Hiv ◽  
Concentration Data ◽  
Flip Flop ◽  
Long Acting ◽  
Living With Hiv

Abstract Objectives To characterize the population pharmacokinetics of the rilpivirine long-acting (LA) formulation after intramuscular administration. Methods Rich and sparse rilpivirine plasma concentration data were obtained from seven clinical studies. In total, 18 261 rilpivirine samples were collected from 986 subjects (131 healthy subjects from Phase I studies and 855 people living with HIV from Phase IIb/III studies). Doses ranged from 300 to 1200 mg, as single-dose or multiple-dose regimens (every 4 or 8 weeks). In Phase III studies, an initiation injection of 900 mg followed by continuation injections of 600 mg every 4 weeks was used. Non-linear mixed-effects modelling was performed using NONMEM® software. Results A one-compartment model with linear elimination and two parallel absorption pathways (fast and slow) with sequential zero-first-order processes adequately captured rilpivirine flip-flop pharmacokinetics after intramuscular administration of the LA formulation. The estimated apparent elimination half-life of rilpivirine LA was 200 days. None of the evaluated covariates (age, body weight, BMI, sex, race, health status and needle length) had a clinically relevant impact on rilpivirine pharmacokinetics. Conclusions The population pharmacokinetic model suitably describes the time course and associated variability of rilpivirine plasma concentrations after rilpivirine LA intramuscular administration. The monthly regimen consists of an oral lead-in period (rilpivirine 25 mg tablets once daily for 4 weeks), followed by an initiation injection of 900 mg rilpivirine LA, then 600 mg rilpivirine LA continuation injections monthly. The absence of a clinically relevant effect of covariates on rilpivirine pharmacokinetics suggests that rilpivirine LA dose adjustments for specific subgroups are not warranted.

scholarly journals Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Patients with Pneumonia, Bloodstream Infection/Sepsis, or Complicated Urinary Tract Infection

2020 ◽  
Author(s):  
Nao Kawaguchi ◽  
Takayuki Katsube ◽  
Roger Echols ◽  
Toshihiro Wajima
Keyword(s):  
Urinary Tract Infection ◽  
Renal Function ◽  
Urinary Tract ◽  
Tract Infection ◽  
Bloodstream Infection ◽  
Plasma Concentrations ◽  
Complicated Urinary Tract Infection ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Population Pk

Cefiderocol is a novel siderophore cephalosporin with antibacterial activity against Gramnegative bacteria including carbapenemresistant strains. The standard dosing regimen of cefiderocol is 2 g administered every 8 hours over 3 hours infusion in patients with creatinine clearance (CrCL) of 60 to 119 mL/min, and it is adjusted for patients with < 60 mL/min or ≥ 120 mL/min CrCL. A population pharmacokinetic (PK) model was constructed using 3427 plasma concentrations from 91 uninfected subjects and 425 infected patients with pneumonia, bloodstream infection/sepsis (BSI/sepsis), and complicated urinary tract infection (cUTI). Plasma cefiderocol concentrations were adequately described by the population PK model, and CrCL was the most significant covariate. No other factors including infection sites and mechanical ventilation were clinically relevant, although the effect of infection sites was identified as a statistically significant covariate in the population PK analysis. No clear pharmacokinetic/pharmacodynamic relationship was found for any of the microbiological outcome, clinical outcome, or vital status. This is because the estimated percentage of time for which free plasma concentrations exceed the minimum inhibitory concentration (MIC) over dosing interval (%fT>MIC) was 100% in most of the enrolled patients. The probability of target attainment (PTA) for 100% fT>MIC was > 90% against MICs ≤ 4 μg/mL for all infection sites and renal function groups except for BSI/sepsis patients with normal renal function (85%). These study results support adequate plasma exposure can be achieved at the cefiderocol recommended dosing regimen for the infected patients including the patients with augmented renal function, ventilation, and/or severe illness.

scholarly journals 27 A New Method for Initiating Treatment with the Long-acting Antipsychotic Aripiprazole Lauroxil

CNS Spectrums ◽  
2019 ◽  
Vol 24 (1) ◽  
pp. 188-189 ◽  
Author(s):  
Jonathan Meyer ◽  
Rakesh Jain ◽  
Angela Wehr ◽  
Bhaskar Rege ◽  
Lisa von Moltke ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Treatment Initiation ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Particle Diameter ◽  
Systemic Circulation ◽  
Population Pharmacokinetic ◽  
Suitable Alternative ◽  
Study Objective ◽  
Long Acting

AbstractSTUDY OBJECTIVESlow release is a fundamental feature of long-acting injectable (LAI) antipsychotics. This property allows continuous drug exposure between dosing intervals. However, there can be a significant delay between giving the first LAI dose and achievement of efficacious plasma concentrations. This time period requires additional pharmacologic intervention. Until now, this delay was addressed with one of two strategies: 1) continuing with supplemental oral antipsychotic, or 2) giving more LAI up front (e.g. loading dose). A third strategy has now been developed to reduce the time needed for oral supplementation when starting the LAI aripiprazole lauroxil (AL) from 21days to 1day. A nano-crystalline milled dispersion of AL (ALNCD; brand name ARISTADA INITIO™) was formulated by reducing the AL particle diameter from micron-size particles to nanometer- sized particles. ALNCD has faster dissolution and a shorter half-life than AL and is designed to be used as a single injection along with a single oral aripiprazole dose of 30mg as a 1-day alternative to the 21days of oral aripiprazole supplementation. Here we provide an overview of the new 1-day initiation regimen for starting AL treatment, and demonstrate the relative contributions of each of its components.METHODSA blinded, randomized, phase 1, pharmacokinetic (PK), and safety study compared the 1-day initiation regimen with the 21-day oral aripiprazole regimen. A combination of observed data, and population pharmacokinetic model–based simulations were used to plot plasma aripiprazole concentrations of single doses of ALNCD, 30mg oral aripiprazole, and AL, individually, and all three combined.RESULTSThe PK profiles of the 1-day and 21-day initiation regimens (both in conjunction with either 441mg or 882mg doses of AL) were comparable, with therapeutically relevant aripiprazole levels achieved within 4days of treatment initiation. The safety profile of the 1-day initiation regimen was similar to the 21-day initiation regimen, and consistent with that of AL. Aripiprazole concentration–time profiles demonstrated that each component delivered aripiprazole to the systemic circulation at different time periods, with the 30mg dose of oral aripiprazole predominant in the first week, followed by ALNCD, and then AL.CONCLUSIONSThe 1-day initiation regimen is well-tolerated and a suitable alternative to 21days of oral aripiprazole supplementation for starting AL. Each component of the 1-day initiation regimen, together with AL, is necessary to provide continuous coverage from treatment initiation until the next regularly scheduled AL injection.Funding Acknowledgements: This study was funded by Alkermes Inc.

scholarly journals Pharmacokinetics and antiviral activity of cabotegravir and rilpivirine in cerebrospinal fluid following long-acting injectable administration in HIV-infected adults

2019 ◽  
Vol 75 (3) ◽  
pp. 648-655 ◽  
Author(s):  
Scott L Letendre ◽  
Anthony Mills ◽  
Debbie Hagins ◽  
Susan Swindells ◽  
Franco Felizarta ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Steady State ◽  
Antiviral Activity ◽  
Plasma Concentrations ◽  
Integrase Inhibitor ◽  
Virological Suppression ◽  
Hiv Integrase ◽  
Long Acting ◽  
Hiv 1

Abstract Background Long-acting (LA) formulations of cabotegravir, an HIV integrase inhibitor, and rilpivirine, an NNRTI, are in development as monthly or 2 monthly intramuscular (IM) injections for maintenance of virological suppression. Objectives To evaluate cabotegravir and rilpivirine CSF distribution and HIV-1 RNA suppression in plasma and CSF in HIV-infected adults participating in a substudy of the Phase 2b LATTE-2 study (NCT02120352). Methods Eighteen participants receiving cabotegravir LA 400 mg + rilpivirine LA 600 mg IM [every 4 weeks (Q4W), n = 3] or cabotegravir LA 600 mg + rilpivirine LA 900 mg IM [every 8 weeks (Q8W), n = 15] with plasma HIV-1 RNA &lt;50 copies/mL enrolled. Paired steady-state CSF and plasma concentrations were evaluable in 16 participants obtained 7 (±3) days after an injection visit. HIV-1 RNA in CSF and plasma were assessed contemporaneously using commercial assays. Results Median total CSF concentrations in Q4W and Q8W groups, respectively, were 0.011 μg/mL and 0.013 μg/mL for cabotegravir (0.30% and 0.34% of the paired plasma concentrations) and 1.84 ng/mL and 1.67 ng/mL for rilpivirine (1.07% and 1.32% of paired plasma concentrations). Cabotegravir and rilpivirine total CSF concentrations exceeded their respective in vitro EC50 for WT HIV-1 (0.10 ng/mL and 0.27 ng/mL, respectively). All 16 participants had HIV-1 RNA &lt;50 copies/mL in plasma and CSF, and 15 of 16 participants had HIV-1 RNA &lt;2 copies/mL in CSF. Conclusions A dual regimen of cabotegravir LA and rilpivirine LA achieved therapeutic concentrations in the CSF resulting in effective virological control in CSF.

scholarly journals Pharmacokinetics of Chloroquine and Monodesethylchloroquine in Pregnancy

2010 ◽  
Vol 54 (3) ◽  
pp. 1186-1192 ◽  
Author(s):  
Harin A. Karunajeewa ◽  
Sam Salman ◽  
Ivo Mueller ◽  
Francisca Baiwog ◽  
Servina Gomorrai ◽  
...  
Keyword(s):  
High Performance ◽  
Plasma Concentrations ◽  
Population Pharmacokinetic ◽  
Presumptive Treatment ◽  
Time Curve ◽  
Population Pharmacokinetic Modeling ◽  
Elimination Half ◽  
Intermittent Presumptive Treatment ◽  
Papua New Guinean ◽  
In Pregnancy

ABSTRACT In order to determine the pharmacokinetic disposition of chloroquine (CQ) and its active metabolite, desethylchloroquine (DECQ), when administered as intermittent presumptive treatment in pregnancy (IPTp) for malaria, 30 Papua New Guinean women in the second or third trimester of pregnancy and 30 age-matched nonpregnant women were administered three daily doses of 450 mg CQ (8.5 mg/kg of body weight/day) in addition to a single dose of sulfadoxine-pyrimethamine. For all women, blood was taken at baseline; at 1, 2, 4, 6, 12, 18, 24, 30, 48, and 72 h posttreatment; and at 7, 10, 14, 28, and 42 days posttreatment. Plasma was subsequently assayed for CQ and DECQ by high-performance liquid chromatography, and population pharmacokinetic modeling was performed. Pregnant subjects had significantly lower area under the plasma concentration-time curve for both CQ (35,750 versus 47,892 μg·h/liter, P < 0.001) and DECQ (23,073 versus 41,584 μg·h/liter, P < 0.001), reflecting significant differences in elimination half-lives and in volumes of distribution and clearances relative to bioavailability. Reduced plasma concentrations of both CQ and DECQ could compromise both curative efficacy and posttreatment prophylactic properties in pregnant patients. Higher IPTp CQ doses may be desirable but could increase the risk of adverse hemodynamic effects.

Advancements in Treatment for Newly Diagnosed Frail and Elderly Myeloma Patients: A Systematic Review

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5589-5589
Author(s):  
Syed Maaz Abdullah ◽  
Tariq Iqtidar Sadiq Syed ◽  
Muhammad Salman Faisal ◽  
Awais Ijaz ◽  
Syeda Sabeeka Batool ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Phase Iii ◽  
Two Phase ◽  
Phase Iii Trial ◽  
Frail Patients ◽  
Best Response ◽  
Drug Regimens ◽  
Grade 3

Introduction: About 60% newly diagnosed multiple myeloma (NDMM) cases are above age of 60 years. The paucity of studies exclusively targeting management of frail patients has led to persistence of therapeutic uncertainties. With data on more than ten thousand patients, purpose of this review is to summarize the available therapeutic options with emphasis on recent advances for treatment of frail and elderly, transplant ineligible NDMM patients. Methods: We performed a comprehensive literature search on June 1st, 2019 on PubMed, Cochrane Library and ClinicalTrials.gov. We used the MeSH terms: 'Multiple Myeloma' and 'Frail Elderly', with associated entry words. Search yielded 71 studies regarding our topic of interest. Following PRISMA guidelines and subsequent screening by two reviewers, we shortlisted 19 ongoing/completed studies (n=10297) and included data from these studies in our systematic review. Results: Two/Three Drug regimens: Among the two drug regimens [Table 1], Lenalidomide (R) and Dexamethasone (D) (RD) combination has been most widely studied (n=1445). RD yielded objective response rate (ORR) of 81.3%, complete response (CR) or above of 24.9% and progression free survival (PFS) of 31.9 months in a phase III trial (Usmani, 2019) (n=369). Facon et al. (2019) [n=368] used Daratumumab (Dara)+R+D (DaraRD) which exhibited the best response overall with an ORR of 92.9%, CR of 47.6%, VGPR of 31.8% while the PFS was not reached till study end point. However, >grade 3 neutropenia developed in 50% patients. Three-drug regimen of Bortezomib(V)+Melphalan(M)+Prednisolone(P) (VMP) has been the most widely studied regimen (n=1059) in four phase II/III clinical trials. In a phase II trial (Kizaki, 2016) (n=87), VMP yielded a PFS of 36 months and CR of 25%. In a Phase II trial by Larocca et al (2016, n=148), 3 cohorts (VP, V+ Cyclophosphamide (C) +P and VMP respectively) were studied. Best response was achieved by VMP with ORR of 86%, PFS of 17.1 months and CR of 14%, compared with VCP (ORR=67%, PFS=15.2 months and CR=2%) and VP (ORR=64%, PFS=14 months, CR=8%). However, the discontinuation rate (DR) due to AEs for VMP was relatively high (20%). A phase III trial (San-Miguel, 2018) (n=955) compared Carfilzomib(K)+M+P (KMP) against VMP. Median PFS was found to be 22.3 months with KMP Vs 22.1 months with VMP. Grade ≥3 AE rates were 74.7% for KMP and 76.2% for VMP. Thus, the results showed no significant difference between both regimens. Thalidomide (T) has also been used in three drug combinations in two phase II/III trials (n=667). Ixazomib(I)+T+D (ITD) in a phase II trial (Abildgaard, 2017) (n=120) revealed an ORR of 75% compared to ORR of 62% in a phase III trial (Benboubker et al, 2014) (n=547) using MPT. Notable >grade 3 AEs with ITD were infections (15%) and cardiac abnormalities (10%) while with MPT were >grade 3 neutropenia (45%) and infections (17%). A retrospective analysis by Facon et al. (2015, n=1517) comparing RD Vs MPT demonstrated that RD reduced the risk of progression or death by 21% compared to MPT in frail patients. 2. Four Drug Regimens: Four drug regimens have also been used in transplant-ineligible patients in two phase II/III trials (n=583). Mateos et al. (2015, n=233) conducted a phase II trial in which patients were treated with VMP+RD (VMPRD). 49 frail patients based on Age >80 years (IMWG criteria) had ORR of 68%, PFS of 25 months and CR of 10%, with a DR of 63% due to toxicity or informed consent withdrawal. However, in the ALCYONE trial (San-Miguel, 2017) (n=350), use of Dara+VMP (DaraVMP) resulted in ORR of 90.9%, ≥CR of 42.6%, VGPR of 28.6% and PFS was not reached till study end point. Furthermore, the DR due to AEs for DaraVMP was also lesser (4.9%). Various trials [Table 2] are being conducted to establish correlation of frailty scores with parameters of efficacy. Conclusion: Management of frail and elderly NDMM patients is challenging as there is need to individualize therapy for this group. Novel agents such as lenalidomide, bortezomib and daratumumab have shown promising efficacy when used as combination therapies with other conventional agents. Intensity of treatment and efficacy goals should be tailored to the functional capacity and tolerance of each individual patient. There is need for focused clinical trials for this group in terms of greater recruitment into clinical trials to establish better correlation between frailty status and efficacy, and consolidating evidence for improved patient care. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Efficacy of Daratumumab Based Regimens Compared to Standard of Care for Transplant Ineligible Newly Diagnosed Multiple Myeloma in Phase III Clinical Trials: A Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Zahoor Ahmed ◽  
Karun Neupane ◽  
Rabia Ashraf ◽  
Amna Khan ◽  
Moazzam Shahzad ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Standard Care ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Control Group ◽  
Two Phase ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Phase Iii Clinical Trials

Introduction: Daratumumab (Dara) is a human anti-CD38 monoclonal antibody approved for multiple myeloma (MM) treatment. Dara has a promising efficacy and a favorable safety profile in newly diagnosed MM (NDMM) patients. This study is focused on the efficacy and safety of Dara when added to the standard care regimen in transplant ineligible NDMM in phase III clinical trials. Methods: We performed a comprehensive database search on four major databases (PubMed, Embase, Cochrane, and Clinicaltrials.gov). Our search strategy included MeSH (Medical Subject Headings) terms and key words for multiple myeloma and Dara including trade names and generic names from date of inception to May 2020. Initial search revealed 587 articles. After excluding review articles, duplicates, and non-relevant articles, two phase III clinical trials were included which reported overall response rate (ORR), and progression free survival (PFS) of transplant ineligible NDMM patients with Dara addition to standard care regimen. Odds ratios (OR) of ORR were computed and hazard ratios (HR) of PFS (along with 95% confidence intervals; CI) were extracted to compute a pooled HR using a fixed effect model in RevMan v.5.4. Results: A total of 1453 transplant ineligible NDMM patients were enrolled and evaluated in two phase III randomized clinical trials. Seven hundred and eighteen patients were in Dara group and 735 patients were in control group. Bahlis et al. (2019) studied Dara + lenolidamide (R) and dexamethasone (d) vs Rd in NDMM pts (n=737) in MAIA phase III trial. Similarly, Mateos et al. (2018) reported the role of Dara + bortezomib (V) + melphalan (M), and prednisone (P) vs VMP in NDMM pts (n=706) in a phase III trial (Alcyone). A pooled analysis of these phase III trials showed ORR (OR: 3.26, 95% CI 2.36-4.49; p &lt; 0.00001, I2 = 0%), and progression free survival (PFS) (HR: 0.53, 95% CI 0.43-0.65; p &lt; 0.00001, I2 = 0%). Achievement of minimal residual disease (MRD) negative status was significant in Dara based regimen as compared to control group (OR: 4.49, 95% CI 3.31-6.37; p &lt; 0.00001, I2 = 0%). Dara addition to standard care regimen (Rd and VMP) decreased the risk of progression/death to 42% (HR: 0.58, 95% CI 0.48-0.70; p &lt; 0.00001, I2 = 0%). The addition of Dara increased the risk of neutropenia (OR: 1.41, 95% CI 1.07-1.85; p &lt; 0.02, I2 = 44%), and pneumonia (OR: 2.25, 95% CI 1.54-3.29; p &lt; 0.0001, I2 = 37%) vs control group. However, decreased risk of anemia (OR: 0.64, 95% CI 0.49-0.85: p &lt; 0.002, I2=30%) was observed in Dara group vs control group (Figure 1). Conclusion: Addition of Dara to the standard care regimen for transplant ineligible NDMM achieved the surrogate end points with improved efficacy and MRD negative status with manageable toxicity. However, data from more randomized controlled trials is needed. Table Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Effect of PSA-tricom, a pox-viral vaccine in prostate cancer (PCa), on tumor growth rates within 80 days after initiation in nonmetastatic PCa.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 57-57 ◽  
Author(s):  
James L. Gulley ◽  
Ravi Amrit Madan ◽  
Wilfred Donald Stein ◽  
Julia Wilkerson ◽  
William L. Dahut ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Iii ◽  
Clinical Activity ◽  
Short Term ◽  
Two Phase ◽  
Phase Iii Trial ◽  
Castration Resistant ◽  
Viral Vaccine ◽  
Immune Therapies

57 Background: Our understanding of immunotherapies for prostate cancer (PSA-TRICOM, sipuleucel-T, ipilimumab) is incomplete in that such therapies have improved overall survival (OS) without changes in time to progression (TTP) in randomized trials. In an effort to better understand this discrepancy, we evaluated data from studies of PSA-TRICOM. A pox viral vaccine expressing PSA and 3 T-cell co-stimulatory molecules, PSA-TRICOM has demonstrated PSA-specific immune responses and evidence of clinical activity that supported initiation of a currently accruing Phase III trial. An analysis of NCI PCa trials (including a PSA-TRICOM trial) suggests that immune therapies may eventually slow the growth rate (GR) of tumors, leading to unaltered short term TTP, yet improved OS (Stein et al. Clin Can Res. 2011). Methods: PSA-TRICOM was administered to 50 hormone-naïve patients (pts.) with non-metastatic, castration naive PCa in a multi-center trial (ECOG 9802). Pts were treated every 4 weeks for 3 months, then every 12 weeks (preliminary data previously reported, DiPaola, RS et al. ASCO GU 2009). PSA values were used to calculate tumor GR within the first 100 days of treatment. (Pts were given no additional therapies during this time.) As previously described, a two-phase mathematical equation yielded concomitant PSA GR and regression rate constants.(Stein et. al., 2011) Results: See Table. Conclusions: These data suggest that PSA-TRICOM can alter GR significantly within 3 months. If confirmed in future trials, it could explain why vaccines have demonstrated improved OS without improved TTP. A slowing of the GR may not lead to substantial differences in short term TTP, but may enhance OS in the long term. This concept will be evaluated in an international Phase III trial of PSA-TRICOM in minimally symptomatic, metastatic castration-resistant PCa that is currently recruiting pts. Clinical trial information: NCT00108732. [Table: see text]

scholarly journals Pharmacokinetic Properties of Sulfadoxine-Pyrimethamine in Pregnant Women

2009 ◽  
Vol 53 (10) ◽  
pp. 4368-4376 ◽  
Author(s):  
Harin A. Karunajeewa ◽  
Sam Salman ◽  
Ivo Mueller ◽  
Francisca Baiwog ◽  
Servina Gomorrai ◽  
...  
Keyword(s):  
High Performance ◽  
Plasma Concentrations ◽  
Population Pharmacokinetic ◽  
Third Trimester ◽  
Presumptive Treatment ◽  
Time Curve ◽  
Population Pharmacokinetic Modeling ◽  
Pharmacokinetic Properties ◽  
Intermittent Presumptive Treatment ◽  
Papua New Guinean

ABSTRACT To determine the pharmacokinetic disposition of sulfadoxine (SDOX) and pyrimethamine (PYR) when administered as intermittent presumptive treatment during pregnancy (IPTp) for malaria, 30 Papua New Guinean women in the second or third trimester of pregnancy and 30 age-matched nonpregnant women were given a single dose of 1,500 mg of SDOX plus 75 mg of pyrimethamine PYR. Blood was taken at baseline and 1, 2, 4, 6, 12, 18, 24, 30, 48, and 72 h and at 7, 10, 14, 28, and 42 days posttreatment in all women. Plasma samples were assayed for SDOX, N-acetylsulfadoxine (NASDOX), and PYR by high-performance liquid chromatography. Population pharmacokinetic modeling was performed using NONMEM v6.2.0. Separate user-defined mamillary models were fitted to SDOX/NASDOX and PYR. When the covariate pregnancy was applied to clearance, there was a significant improvement in the base model for both treatments. Pregnancy was associated with a significantly lower area under the concentration-time curve from 0 to ∞ for SDOX (22,315 versus 33,284 mg·h/liter), NASDOX (801 versus 1,590 mg·h/liter), and PYR (72,115 versus 106,065 μg·h/liter; P < 0.001 in each case). Because lower plasma concentrations of SDOX and PYR could compromise both curative efficacy and posttreatment prophylaxis in pregnant patients, IPTp regimens incorporating higher mg/kg doses than those recommended for nonpregnant patients should be considered.

scholarly journals New Colistin Population Pharmacokinetic Data in Critically Ill Patients Suggesting an Alternative Loading Dose Rationale

2014 ◽  
Vol 58 (12) ◽  
pp. 7324-7330 ◽  
Author(s):  
N. Grégoire ◽  
O. Mimoz ◽  
B. Mégarbane ◽  
E. Comets ◽  
D. Chatelier ◽  
...  
Keyword(s):  
Steady State ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Loading Dose ◽  
Liquid Chromatography Tandem Mass

ABSTRACTColistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventy-three critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (Cmax) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t1/2) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate.

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