Pharmacokinetic Profile In Patients Research Articles

A Real-World Population Pharmacokinetic (PK) Study of Two Recombinant Factor VIII (rFVIII) Concentrates in Boys with Severe Hemophilia a without Inhibitors

Introduction To personalize long-term prophylaxis in boys with hemophilia A with a severe bleeding phenotype, the individual's pharmacokinetic (PK) profile must be established. Traditional FVIII PK assessment has required a 2-3-day washout, which can place boys at risk of bleeding, and up to 11 post-infusion blood samples collected over a 48h period (Lee et al., ISTH guidelines, 2001). Population PK models with Bayesian forecasting are currently available that permit the use of a no-washout PK protocol with sparse sampling, which is clinically practical and less demanding for patients and their families. Our previous experience with a no-washout, single-clinic visit, reverse 2-sampling time point (24 and 3h) PK protocol established that this practical, patient-friendly PK protocol was sufficiently accurate for generating clinically useful individual PK profiles in patients receiving a standard half-life (SHL) FVIII concentrate [antihemophilic factor (recombinant) plasma/albumin-free method (Advate®)] for long-term prophylaxis (Blanchette et al., Thromb Haemost, 2021). Aim To determine the accuracy of a clinically practical single-clinic visit, reverse 2-sampling time point population PK protocol for generating individual PK profiles [clearance (Cl) and terminal half-life (t1/2)] in boys with severe hemophilia A without inhibitors receiving either an SHL [antihemophilic factor (recombinant) BAY 81-8973 (Kovaltry®)] or an extended half-life (EHL) FVIII concentrate [antihemophilic factor (recombinant) PEGylated BAY 94-9027 (Jivi®)] for long-term prophylaxis. Methods In this multicenter observational study, participants had their first infusion given at home. Of a total of 14 boys with hemophilia A without inhibitors receiving long-term prophylaxis, 5 receiving a SHL completed a single clinic visit, reverse 2-point (24 and 3h) and a multiple clinic visit 6-point (baseline, 1, 3, 8, 24 and 48h) PK sampling protocol; and 4 boys completed a SHL single clinic visit reverse 2-point (48 and 3h) and a 2 clinic visit reverse 3-point (48, 3 and 24h) PK sampling protocol. 5 boys receiving EHL completed single clinic visit, reverse 2-point (72 and 3h) and 2-clinic visit 3-point (72, 3 and 48h) PK sampling protocols and they had multiple spot samplings (n=12) at various post-infusion times to evaluate the precision of their predicted PK profiles based on their 2-point PK sampling protocol. One-stage (OS) and chromogenic (CHR) FVIII:C and von Willebrand factor antigen (VWF:Ag) assays were performed in a central reference coagulation laboratory in Kingston, Ontario. PK parameters (Cl and t1/2) were estimated using the WAPPS-Hemo population PK program. The median of the % difference between the 2-sampling time point PK protocol compared to the 6- and 3- sampling time point PK protocols is reported. Results 14 boys with hemophilia A (FVIII:C <2%; median age: 14.5 yrs, range: 5-19 yrs) participated in the study. The 2-point PK protocol for both SHL and EHL showed a higher Cl and lower t1/2 when compared to either a 6-sampling time point (for SHL) or a 3-sampling time point (for either SHL or EHL) PK assessment (Table 1). The difference was greatest for the 2-point (24 and 3h) vs the 6-point (Table 1). In the case of the 2-point (48 and 3h for SHL and 72 and 3h for EHL) vs 3-point (an additional 24h time point for SHL and 48h for EHL) PK parameter estimates, the 2-point protocol gave values that were all within 6% of those obtained with the 3-sampling time point PK (Table 1). The OS and CHR assays gave similar estimations for Cl and t1/2 with the exception of t1/2 when comparing the 6-point to the 2-point PK protocol (Table 1). Evaluation of the 2-sampling time point PK protocol through spot sampling showed approximately 66% and 81% of FVIII:C values falling within the 95% prediction limits for the OS and CHR assays, respectively (n=12 for EHL OS; n=11 for EHL CHR). There was a strong association between the observed FVIII:C levels from the spot sampling and their predicted values from the 2-point PK for EHL (R2=94% and 71% for the OS and CHR assays, respectively) (Fig. 1). Conclusion The reverse 2-point, single clinic visit, PK protocol (24/48 or 72h and 3h) is a practical approach to generate PK parameters that provide clinically useful information for guiding personalized prophylaxis regimens for boys receiving SHL or EHL for long-term prophylaxis. Funding Supported by Bayer (Investigator-Initiated Research grant) Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Potent Small Molecule Inhibitor of FLT3, PHI-101 Overcomes Resistance in Acute Myeloid Leukemia: Efficacy and PK/PD Profile in Phase 1 First in Human Study

Background: Mutations in FMS-like tyrosine kinase 3 (FLT3) are found in approximately 25-35% of acute myeloid leukemia (AML) patients and are often associated with relapse and poor prognosis. PHI-101 is an orally active, potent small molecule Type I FLT3 tyrosine kinase inhibitor (TKI) developed to overcome resistance in AML. It selectively inhibits both FLT3-ITD mutations and a wide variety of FLT3 point mutations in TKD in preclinical AML models. PHI-101 showed increased anti-leukemic activity compared to gilteritinib in both in vitro and in vivo studies with AML patient-derived primary leukemic cells. Phase 1 global clinical trials for PHI-101 (NCT04842370) against refractory and relapsed (R/R) AML are currently ongoing to assess the overall safety and efficacy. Study Design and Methods: Eligible subjects, regardless of FLT3 mutation status, were enrolled at each dose level in phase 1a to evaluate dose-limiting toxicities (DLTs) during the 28-day daily dosing period according to an accelerated 3+3 design. A dose escalation to the next dose level proceeds upon the recommendation of the safety monitoring committee. Blood samples from patients were collected to evaluate the concentration of PHI-101 in plasma during the 24-h observation period after the initial dose (cycle1, day1) and after multiple doses (cycle1, day15). A pharmacodynamic evaluation of serial plasma samples via a plasma inhibitory assay (PIA) was used to assess the FLT3-inhibitory activity of PHI-101 in FLT3-mutant cell lines. The variant allele frequency (VAF) analysis for FLT3-ITD, FLT3-TKD and other AML-related mutant in the population was performed using next-generation sequencing (NGS) technology in accordance with instructions for HEMEaccuTestTM IVD kit, with bone marrow aspirate samples collected from the patients before and after PHI-101 treatment. Results: To date, 10 enrolled patients with R/R AML have been evaluated for safety assessment at four dose levels in the dose-escalation phase 1a clinical trial of PHI-101, and they have not experienced any DLTs from daily doses of the 28-day cycle. Seventy percent of enrolled patients had more than 3 prior anti-leukemic treatment attempts, and four patients had relapsed or refractory disease after treatment with other FLT3 inhibitors including gilteritinib, quizartinib, or HM43239. The median percentage of blasts at the time of enrollment was 71%, and the median duration on study with PHI-101 was 83 days. After 1 cycle of PHI-101 treatment, bone marrow blasts were reduced by up to 98%, and the responses extended to patients who had relapsed after treatment with other FLT3 targeted therapeutics. Clinical benefits, including improvement of hematological parameters, were observed in five patients who harbored FLT3 mutations. PHI-101 exhibits a dose-proportional pharmacokinetic profile in patients. The median maximum concentration was reached 4-6h following dosing of PHI-101, and the accumulated concentration of PHI-101 in plasma on day 15 of treatment was 3-5 times higher than on day 1. Estimated T1/2 and Tmax did not appear to be dose dependent. The concomitant plasma inhibitory assay (PIA) and PK data demonstrated that exposure-related inhibition of FLT3 phosphorylation of at least 90% by plasma PHI-101 was seen within 6 hours after a single dose as long as the plasma concentration of PHI-101 reached at least 70 ng/mL. The patients with FLT3-ITD or TKD mutations showed clinical reductions of FLT3 mutation VAF of up to 77% and leukemic blast reductions of up to 87% during the same period. Notably, PHI-101 treatment significantly cleared the FLT3-N676K mutation by 96% in addition to FLT3-D835Y mutations. Conclusion: A dose-escalating phase 1a clinical data of PHI-101, which reflects up to cohort 4 of the study, indicates that PHI-101 generated potent FLT3 inhibition leading to encouraging anti-leukemic responses in R/R AML patients, including in those with prior FLT3 TKI therapeutic failure. PHI-101 showed good tolerance and favorable safety profile and reduced leukemic blasts significantly with 28-day dosing. PHI-101 sustained its activity to clear FLT3-ITD and/or FLT3-TKD mutations including D835Y or N676K identified in AML patients. Oral PHI-101 treatment results in a dose-dependent PK profile and clinically relevant efficacy of FLT3 phosphorylation inhibition. This trial indicates that PHI-101 is a next generation of FLT3 inhibitor effective for R/R AML patients.

P322 Effectiveness of Tumor Necrosis Factor-alpha inhibitors and Thiopurines combination therapy according to, 6-thioguanine nucleotides plasma levels: A Systematic Review

Abstract Background Inflammatory bowel diseases (IBD), Crohn’s disease (CD) and Ulcerative Colitis (CU), have a progressive course with a significant percentage of primary or secondary failure to anti- tumor necrosis factor (TNF). It is already known that the combination therapy with anti-TNF and thiopurines have shown more effectiveness than monotherapy, especially with Infliximab (IFX). Thiopurines activity optimization, by the, 6-thioguanine nucleotides (6-TGN) measurement, have been related to better clinical outcomes in monotherapy, but evidence is lacking regarding combination therapy. Our aim was assessing the clinical and pharmacokinetic outcomes of the combination therapy regarding (6-TGN) serum levels. Methods We performed a systematic review in electronic resources in three major databases (PUBMED, Cochrane and Web of Science) up to, 18 January, 2021 using MeSH terms, text terms and specific outcomes without restrictions for year or language. We searched for randomized clinical trials (RCT) and observational studies. Outcomes included clinical remission, clinical relapse, mucosal healing, anti-TNF serum levels, antibodies to anti-TNF and adverse events regarding, 6-TGN serum levels. Studies without, 6-TGN measurement were excluded. Results Our search identified, 14 studies (three RCT and, 11 observational studies). Eight (57.1%) studies in Crohn’s disease patients. Seven (50.0%) publications included patients with IFX, and, 5 (35.7%) with adalimumab (ADA). Most of the studies showed a positive association between, 6-TGN serum levels and clinical remission in patients with IFX treatment. Higher, 6-TGN serum levels improved the pharmacokinetic profile in patients with both anti-TNF. The target, 6-TGN serum levels proposed for the pharmacokinetic outcomes were lower (125–200 pmol/, 8 ×, 108 RBC) than those for clinical remission (230 -, 450 pmol/, 8 ×, 108 RBC). Conclusion This systematic review shows that adequate, 6-TGN serum levels are associated with clinical response and better pharmacokinetic outcomes in combination therapy with IFX, with a weaker association with ADA therapy. Lower, 6-TGN serum levels could be enough to avoid unfavorable pharmacokinetic evolution with anti-TNF, especially IFX. There is not enough data supporting lower thiopurines doses for clinical outcomes, nor even to avoid adverse events. Further, well-designed research is needed to confirm the importance of, 6-TGN monitoring to optimize the combination therapy with anti-TNF and to decrease thiopurine doses when possible.

Abstract 5225: Temporal inhibition of ERK is sufficient for tumor growth inhibition in KRAS-mutant or BRAF-mutant tumors

Abstract The combination of BRAF and MEK inhibitors have been clinically studied, and three different combinations (dabrafenib plus trametinib, vemurafenib plus cobimetinib and encorafenib plus binimetinib) are approved by the FDA for treatment of melanoma patients with BRAF V600E mutation. Published reports indicate that each combination has a different efficacy and toxicity profile. It is believed that the toxicity profile of some of these drugs is linked to their pharmacokinetic (PK) profile leading to prolonged pharmacodynamics (PD) or target inhibition. ERK inhibitors have been discovered recently to overcome the acquired resistance to BRAF plus MEK inhibitors in BRAF-mutant melanoma and for combination therapies in RAS/MAPK altered cancers including KRAS-mutant cancers. Several ERK inhibitors have entered clinical development as monotherapy or in combination. However, it is not clear what the minimum time on target is required for efficacy without causing significant toxicity, and whether that would differentiate the therapeutic index of one inhibitor from another. Therefore, we have conducted PK-PD-efficacy relationship studies of different MEK and ERK inhibitors with different PK profiles in mice in BRAF-mutant or KRAS-mutant xenograft models to determine the minimum time on target required for efficacy. We have tested the PK-PD-efficacy of MEK inhibitors trametinib and cobimetinib, as well as ERK inhibitors BVD-523, GDC-0994 and LY3214996 in BRAF V600E or KRAS mutant xenograft models including A375 BRAF V600E melanoma, Colo205 BRAF V600E colorectal carcinoma and HCT116 KRAS G13D colorectal carcinoma. Additionally, an infusion study with LY3214996 was conducted in rats implanted with HCT116 colorectal carcinoma tumors, where drug exposure was controlled for a specified time to get ≥50% pRSK1 inhibition. Our data suggests that ≥50% inhibition of pRSK1 for 8h is required for significant efficacy of ERK inhibitor LY3214996, which is similar to the data presented for GDC-0994 (Robarge K et al, Abstract number DDT02-03, AACR Annual Meeting 2014). Overall assessment of the data in different models suggested that ≥50% target inhibition for 8-16h is enough for significant tumor growth inhibition and regressions by an ERK inhibitor in BRAF-mutant or KRAS-mutant tumors without any obvious toxicity as measured by body weight loss or mortality. LY3214996 is in Phase 1 clinical development and the preliminary PK profile in patients looks as predicted from preclinical data. Therefore, we believe that the PK profile of LY3214996 offers flexibility with dose and schedule to balance efficacy and safety, and to achieve a better therapeutic index in combination therapy for RAS/MAPK pathway altered cancers. Citation Format: Shripad V. Bhagwat, Weihua Shen, Baohui Zhao, Shufen Cai, Lisa Kindler, William T. McMillen, Eunice Yuen, Denis McCann, Jason Manro, Andrew J. Dropsey, Melinda D. Willard, Sajan Joseph, Sheng-Bin Peng. Temporal inhibition of ERK is sufficient for tumor growth inhibition in KRAS-mutant or BRAF-mutant tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5225.

Infliximab Biosimilar (CT-P13; Infliximab-dyyb): A Review in Autoimmune Inflammatory Diseases.

Infliximab biosimilar (CT-P13/infliximab-dyyb; Remsima®, Inflectra®) is approved in several countries for use in all indications for which reference infliximab (Remicade®) is approved, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis, psoriasis, Crohn's disease, and ulcerative colitis. Clinical data contributing to the EU approval of infliximab biosimilar were obtained from two pivotal double-blind clinical trials in patients with AS (PLANETAS) or RA (PLANETRA). Infliximab biosimilar demonstrated equivalence to reference infliximab in terms of its pharmacokinetic profile in patients with AS, patients with RA, and in healthy volunteers, and in terms of its efficacy in patients with RA. Clinical response rates in patients with RA or AS were maintained over the longer term (up to 102weeks). In addition, the efficacy of infliximab biosimilar in patients with RA or Crohn's disease and ulcerative colitis [i.e. inflammatory bowel disease (IBD)] has been demonstrated in the real-world setting. Infliximab biosimilar was generally well tolerated, with a tolerability profile similar to that of reference infliximab. Switching from reference infliximab to infliximab biosimilar had no detrimental effect on efficacy, safety, or immunogenicity compared with continuous infliximab biosimilar therapy, according to the extensions of PLANETAS and PLANETRA, and real-world data in IBD. Current evidence therefore suggests that infliximab biosimilar is a useful alternative to reference infliximab in patients with autoimmune inflammatory diseases.

CT-P13 (an infliximab biosimilar): a guide to its use in the EU

CT-P13 (Remsima™; Inflectra™) is an infliximab biosimilar approved in the EU for use in all indications for which reference infliximab is approved, including rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriatic arthritis and psoriasis. Approval of CT-P13 was based on the results of a rigorous analysis comparing CT-P13 with reference infliximab, including two well-designed clinical trials that demonstrated equivalent efficacy and pharmacokinetic profiles in patients with ankylosing spondylitis and rheumatoid arthritis. As with all biosimilar agents, CT-P13 has the potential to reduce treatment costs relative to those of reference infliximab.

Insulin Degludec: Pharmacokinetic Properties in Subjects with Hepatic Impairment

Background and ObjectiveInsulin degludec is a basal insulin with a slow and distinct absorption mechanism resulting in an ultra-long, flat, and stable pharmacokinetic profile in patients with diabetes mellitus. The aim of this study was to examine the effect of hepatic impairment on the single-dose pharmacokinetics of insulin degludec.MethodsTwenty-four subjects, allocated to one of four groups (n = 6 per group) based on level of hepatic impairment (normal hepatic function, Child–Pugh grade A, B, or C), were administered a single subcutaneous dose of 0.4 U/kg insulin degludec. Blood samples up to 120 h post-dose and fractionated urine samples were collected to measure pharmacokinetic parameters.ResultsNo difference was observed in pharmacokinetic parameters [area under the 120-h serum insulin degludec concentration–time curve (AUC120 h), maximum insulin degludec concentration (C max), and apparent clearance (CL/F)] for subjects with impaired versus normal hepatic function after a single dose of insulin degludec. The geometric mean [coefficient of variation (CV) %] AUC120 h values were 89,092 (16), 83,327 (15), 88,944 (23), and 79,846 (19) pmol·h/L for normal hepatic function and mild, moderate, and severe hepatic impairment, respectively. Simulated steady-state insulin degludec pharmacokinetic profiles showed an even distribution of exposure across a 24-h dosing interval regardless of hepatic function status.ConclusionsThe ultra-long pharmacokinetic properties of insulin degludec were preserved in subjects with hepatic impairment and there were no statistically significant differences in absorption or clearance compared with subjects with normal hepatic function.

Weekly nab-Rapamycin in Patients with Advanced Nonhematologic Malignancies: Final Results of a Phase I Trial

This dose-finding phase I study investigated the maximum-tolerated dose (MTD) and safety of weekly nanoparticle albumin-bound rapamycin (nab-rapamycin) in patients with untreatable advanced nonhematologic malignancies. nab-Rapamycin was administered weekly for 3 weeks followed by 1 week of rest, with a starting dose of 45 mg/m(2). Additional doses were 56.25, 100, 150, and 125 mg/m(2). Of 27 enrolled patients, 26 were treated. Two dose-limiting toxicities (DLT) occurred at 150 mg/m(2) [grade 3 aspartate aminotransferase (AST) elevation and grade 4 thrombocytopenia], and two DLTs occurred at 125 mg/m(2) (grade 3 suicidal ideation and grade 3 hypophosphatemia). Thus, the MTD was declared at 100 mg/m(2). Most treatment-related adverse events (TRAE) were grade 1/2, including thrombocytopenia (58%), hypokalemia (23%), mucositis (38%), fatigue (27%), rash (23%), diarrhea (23%), nausea (19%), anemia (19%), hypophosphatemia (19%), neutropenia (15%), and hypertriglyceridemia (15%). Only one grade 3 nonhematologic TRAE (dyspnea) and one grade 3 hematologic event (anemia) occurred at the MTD. One patient with kidney cancer had a partial response and 2 patients remained on study for 365 days (patient with mesothelioma) and 238 days (patient with neuroendocrine tumor). The peak concentration (Cmax) and area under the concentration-time curve (AUC) of rapamycin increased with dose between 45 and 150 mg/m(2), except for a relatively low AUC at 125 mg/m(2). nab-Rapamycin significantly inhibited mTOR targets S6K and 4EBP1. The clinical dose of single-agent nab-rapamycin was established at 100 mg/m(2) weekly (3 of 4 weeks) given intravenously, which was well tolerated with preliminary evidence of response and stable disease, and produced a fairly dose-proportional pharmacokinetic profile in patients with unresectable advanced nonhematologic malignancies.

A Systematic Screen of FDA-Approved Drugs for Inhibitors of Biological Threat Agents

BackgroundThe rapid development of effective medical countermeasures against potential biological threat agents is vital. Repurposing existing drugs that may have unanticipated activities as potential countermeasures is one way to meet this important goal, since currently approved drugs already have well-established safety and pharmacokinetic profiles in patients, as well as manufacturing and distribution networks. Therefore, approved drugs could rapidly be made available for a new indication in an emergency.Methodology/Principal FindingsA large systematic effort to determine whether existing drugs can be used against high containment bacterial and viral pathogens is described. We assembled and screened 1012 FDA-approved drugs for off-label broad-spectrum efficacy against Bacillus anthracis; Francisella tularensis; Coxiella burnetii; and Ebola, Marburg, and Lassa fever viruses using in vitro cell culture assays. We found a variety of hits against two or more of these biological threat pathogens, which were validated in secondary assays. As expected, antibiotic compounds were highly active against bacterial agents, but we did not identify any non-antibiotic compounds with broad-spectrum antibacterial activity. Lomefloxacin and erythromycin were found to be the most potent compounds in vivo protecting mice against Bacillus anthracis challenge. While multiple virus-specific inhibitors were identified, the most noteworthy antiviral compound identified was chloroquine, which disrupted entry and replication of two or more viruses in vitro and protected mice against Ebola virus challenge in vivo.Conclusions/SignificanceThe feasibility of repurposing existing drugs to face novel threats is demonstrated and this represents the first effort to apply this approach to high containment bacteria and viruses.

The Pharmacokinetics and Pharmacodynamics of Tolvaptan in Patients with Liver Cirrhosis with Insufficient Response to Conventional Diuretics: a Multicentre, Double-blind, Parallel-group, Phase III Study

This study investigated the pharmacokinetic and pharmacodynamic profile of tolvaptan, and verified its efficacy and safety in patients with liver cirrhosis-associated ascites, with insufficient response to conventional diuretic treatment. This multicentre, double-blind, parallel-group study allocated patients with cirrhosis to receive either 3.75 or 7.5 mg/day tolvaptan orally, once daily, for 7 days. Pharmacokinetic, pharmacodynamic and efficacy variables were measured. Tolvaptan was shown to have high plasma concentrations, and prolonged duration of maximum concentration and half life, in these patients with impaired hepatic function. Tolvaptan resulted in dose-dependent decreases in body weight and ascites volume, and increases in urine output. There were no effects on urinary or serum electrolytes. Tolvaptan was well tolerated, with a good safety profile. Tolvaptan at 3.75 mg/day exerts some effects due to the pharmacokinetic profile in patients with liver cirrhosis. Tolvaptan at 7.5 mg/day is a clinically useful option for treating patients who do not respond well to conventional diuretics.

A Pharmacometric Approach to Quantify the Impact of Chronic Kidney Disease and Hemodialysis on Systemic Drug Exposure: Application to Saxagliptin

The draft United States Food and Drug Administration guidance recommends a dedicated pharmacokinetic (PK) study for most drugs intended for use in patients with chronic kidney disease (CKD), including stage V patients requiring hemodialysis (HD) treatment. However, clinical studies conducted in CKD patients are challenged by difficulties in recruiting stage IV and V patients not yet on dialysis, and in balancing patient characteristics among each studied CKD group. Furthermore, study design for dialysis patients often involves a single dose administered before an HD session. The design may not necessarily represent usual patient care in current clinical practice, in which multiple doses are more likely to be administered at varying times between HD sessions. Using exposure modeling of saxagliptin and its active metabolite, 5-hydroxy saxagliptin, as an example, this work illustrates how these challenges can be alleviated by modeling the impact of HD on drug exposure in clinical studies and simulating the expected exposure level in patient care. The modeled PK profiles in dialysis patients were used to understand PK profiles in patients with various CKD stages. The applied pharmacometric approach increased the efficiency of knowledge generation from existing data.

Mogamulizumab for the treatment of adult T-cell leukemia/lymphoma

T-cell neoplasms, such as adult T-cell leukemia/lymphoma (ATL) and peripheral T-cell lymphoma, are particularly aggressive and, despite novel combination chemotherapy regimens, still have extremely poor prognoses. As such, there is an unmet medical need for novel therapies and the anti-chemokine CCR4 receptor antibody mogamulizumab (KW-0761) may offer such an option for the treatment of ATL. Mogamulizumab is a humanized antibody, with a defucosylated Fc region, which enhances antibody-dependent cellular cytotoxicity. As a result, mogamulizumab demonstrates potent antitumor activity at much lower doses than other therapeutic monoclonal antibodies. Clinical testing indicates that mogamulizumab is effective and well tolerated, with a predictable pharmacokinetic profile in patients with relapsed/refractory ATL. This drug was recently granted regulatory approval in Japan for this indication and continues to be evaluated in clinical trials in both the U.S. and Europe.

A phase I study of the novel DNA topoisomerase-1 inhibitor, TLC388, administered intravenously to patients with advanced solid tumors.

e13618 Background: The phase I first-in-human study of TLC388 (Lipotecan) examined the MTD, safety, anti-tumor activity and pharmacokinetic profiles in patients with advanced incurable solid tumors. Methods: Lipotecan was administered intravenously on day 1, 8 and 15 of a 28-day cycle. Patients underwent tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8 and 15 of cycles 1 and 2. Results: Fifty four previously treated patients with advanced or metastatic solid tumors were enrolled The dose was escalated from 1.5 mg/m2 to 60 mg/m2 over 12 patient cohorts. MTD was reached at 50 mg/m2. DLTs above that dose were thrombocytopenia and febrile neutropenia. Treatment was well-tolerated and no accumulated toxicity seen. Treatment related G3/4 hematological toxicity include neutropenia (19%), leucopenia (15%), anemia (9%), and thrombocytopenia (7%). G3/4 non-hematological side effects were diarrhea (2%) and hyponatremia (4%). Twenty one of 35 evaluable patients (60%) continued therapy beyond cycle 2, received a median of 4.5 cycles (2-12 cycles), and had stable disease or minor tumor regression. Prolonged (≥ 6 months) stable disease was noted in 8 patients (23%), including renal (chromophobe and clear cell types), docetaxel refractory prostate, salivary gland, sorafenib refractory hepatic, and vaginal cancers. One minor response occurred in a heavily pretreated 70-year-old male with stage II B thymoma cancer metastatic to lung, liver and lymph nodes who was treated for 12 courses and remains on the study. PET-CT scan revealed tumor size reduction of 22% at cycle 10. Pharmacokinetics of TLC388 was dose-independent; mean (SD) values for the volume of distribution at steady-state and clearance were 857 (1122) L/m2 for S,R-TLC388 and 996 (1333) L/m2 for S,S-TLC388, and 2174 (2526) L/h-m2 for S,R-TLC388 and 2670 (2988) L/h-m2 for S,S-TLC388, respectively. The half-life values averaged 0.67 (1.15) hours for S,R-TLC388 and 0.64 (1.11) hours for S,S-TLC388. Conclusions: Lipotecan at dose of 50 mg/m2 on current treatment schedule is safe, well tolerated, and demonstrates broad antitumor activity to support phase II disease-specific investigations.

Phase I and pharmacokinetic study of weekly oral therapy with vinorelbine in patients with advanced breast cancer (ABC)

A phase I dose-escalation study of a new formulation of oral vinorelbine was conducted to determine the maximum tolerated dose (MTD) of a once weekly regimen and preliminary pharmacokinetic profile in patients with advanced breast cancer (ABC). Twenty-six patients were treated at dose levels ranging from 60 to 100 mg/m2/week. Pharmacokinetics was assessed during the first administration. All patients had histologically confirmed locally advanced or metastatic breast cancer and had received no more than two prior chemotherapy regimens for ABC. The MTD was 100 mg/m2/week due to the occurrence of dose-limiting neutropenia, nausea/vomiting and constipation in five of six patients. Toxicities at 80 mg/m2/week were manageable, neutropenia being the main toxicity (grade 3-4 seen in 10 of 13 patients). Nausea, vomiting and diarrhoea were common but rarely severe. Vinorelbine was rapidly absorbed with maximum blood concentration (Cmax) of 103.8 +/- 41.6 ng x ml(-1) observed 1.2 +/- 0.8 hours (Tmax) after administration of 80 mg/m2. Pharmacokinetic exposure increased linearly with dose. Area under the concentration-time curve (AUC) and concentration measured 24 hours after drug intake (C24h) were significantly correlated with depletion of neutrophils. Objective tumour responses were reported in 6 of the 14 evaluable patients treated at doses > or = 80 mg/m2/week. The safety profile of oral vinorelbine appears comparable to that of intravenous dosing. The recommended phase II dose is 80 mg/m2/week and requires regular monitoring of neutrophil counts.

Pharmacokinetics of oral iloprost in patients with Raynaud’s phenomenon secondary to systemic sclerosis

Iloprost is a chemically stable, pharmacologically highly potent prostacyclin-minietic. The therapeutic efficacy of the intravenous preparation was proven in patients with peripheral arterial occlusive disease or with Raynaud’s phenomenon (RP). Recently, a sustained release oral preparation was developed for outpatient therapy. The purpose of the current study was to investigate whether the oral drug has a different pharmacokinetic profile in patients with RP secondary to systemic sclerosis (SSc) in comparison with healthy volunteers. Ten patients with RP secondary to SSc and 10 healthy volunteers (matched for age and sex) participated. Oral iloprost 50 μg was given twice daily for 8 days with dosing intervals of 5 h and plasma levels were taken over 10 h on Day 1 and 8. Plasma levels of iloprost were determined by a validated specific and sensitive radio-immunoassay. Compared with healthy volunteers, patients with SSc exhibited higher AUC values (by mean factors of 2.1 and 2.0 on Day 1 and 8) and maximum plasma levels (by mean factors of 1.6 and 1.8 on Day 1 and 8). The increased systemic iloprost exposure was observed after both daily doses and on both monitored study days. Mean AUC values did not show accumulation over the 8 days. These findings are in agreement with a reduced total clearance of iloprost given by i.v. route in SSc patients compared to healthy volunteers, although no participant with severe renal impairment was included. A weak but significant correlation was found between individual creatinine clearance and AUC values. In conclusion, RP secondary to SSc is associated with an increased systemic iloprost exposure which is probably caused by changes of the metabolic clearance of iloprost. These effects cannot be explained by changes of renal function alone.

Comparative Efficacy of Two Angiotensin II Receptor Antagonists, Irbesartan and Losartan, in Mild-to-Moderate Hypertension

The primary objectives of this double-blind study were to compare the antihypertensive efficacy and tolerability of irbesartan and losartan, two angiotensin II (AT 1 subtype) receptor antagonists with different pharmacokinetic profiles in patients with mild-to-moderate hypertension. Both drugs are approved for once-daily use (although losartan may also be prescribed twice-daily). After a placebo lead-in, 567 patients were randomized (1:1:1:1) to once-daily therapy with placebo, 100 mg losartan, 150 mg irbesartan, or 300 mg irbesartan for 8 weeks. Treatment groups had comparable demographic and baseline characteristics. After 8 weeks of treatment, reductions from baseline in trough seated diastolic blood pressure (SeDBP) and trough seated systolic blood pressure (SeSBP) with 300 mg irbesartan were greater than with 100 mg losartan ( P < .01 for both comparisons), by 3.0 and 5.1 mm Hg, respectively; larger reductions were also demonstrated at weeks 1 and 4 ( P < .01 and P = .017, respectively, for SeDBP). Throughout the study, the antihypertensive effect of 150 mg irbesartan did not differ significantly from that of 100 mg losartan. All therapies were well tolerated. The 300 mg dose of irbesartan was associated with the lowest incidence of adverse events (AE) and discontinuations because of AE. This study demonstrates that the maximally effective once-daily doses of two different AT 1 receptor antagonists may result in clinically significant differences in blood pressure reductions, and therefore highlights the potential importance of the pharmacokinetic and pharmacodynamic differences between these two members of this class.

Comparison of LH-RH Analogue 1-Month Depot and 3-Month Depot by Their Hormone Levels and Pharmacokinetic Profile in Patients with Advanced Prostate Cancer

In an open, randomized phase II pharmacokinetic study conducted in Germany and Italy, a total of 42 patients with advanced or metastatic prostate cancer (PCa) were treated for 9 months with the luteinizing hormone-releasing hormone analogue (LH-RH-a) leuprorelin acetate depot in two different formulations. Fifteen patients received the 1-month depot and 27 patients received the newly developed 3-month depot, containing 3.75 mg and 11.25 mg, respectively. In both groups, subcutaneous injections of leuprorelin acetate injected monthly or at 3-month intervals produced a complete down-regulation of the pituitary and led to persistent suppression of testosterone and dihydrotestosterone to the castrate range (≤50 ng/dl for testosterone) within the first month of treatment, which thereafter could be maintained over the entire observation period of 9 months. In 10 patients, pretreatment with an antiandrogen for the prevention of clinical flare-up resulted in a slightly more profound and earlier drop in serum testosterone. The 3-month depot showed a higher median peak serum concentration (C_max) of leuprorelin at 20.8 ng/ml than the 1-month depot at 10.7 ng/ml but, conversely, this did not influence the rise in serum testosterone levels. C_max occurred at 3 h for the 3-month and at 1 h for the 1-month depot formulation. During the steady state, constant release could be detected, starting on day 3 and day 7 for the 1-month and 3-month depot, respectively. A marked decrease in median prostate-specific antigen levels of 97.8% (1-month depot) and 96.6% (3-month depot) compared with baseline was observed, indicating an objective clinical response for more than 80% of all patients in both arms. Based on European Organization for Research and Treatment of Cancer criteria, the best response in terms of complete/partial remissions and stabilization was comparable in the two arms at 86.7% (1-month depot) and 85.2% (3-month depot). 6.7% in the 1-month group and 3% in the 3-month depot group showed progression of the disease. The most common side effects in both treatment groups were related to hormone deprivation. Both formulations of the potent LH-RH-a leuprorelin acetate were highly effective in the treatment of advanced PCa and led to comparable endocrine and clinical effects.

853 Ifosfamide in continuous infusion: The pharmacokinetic profile in patients with soft tissue sarcomas

Ifosfamide, an oxazophosphorin compound, active in mesenchimal tumours has recently been used at high doses (14–18 g/sqm) in order to increase the number of responses. Continuous infusion (C.L) of Ifosfamide probably decreases toxicity and increases the therapeutic window of the drug. Bone marrow and renal toxicities seem to be modified greatly by C.L.. Aim of our study has been to characterize the pharmacokinetic drug profile during C.L high dose-fosfamide (HD-IFO). From April to December 1994, 9 patients (pts) with advanced soft tissue sarcomas, 5 pts with osteosarcomas and I pts with Ewing's sarcoma with normal liver and renal function, treated with C.I. HD-IFO (14 g/sqm. over 4 days) and Mesna contemporary infusion, entered into the study. 33 chemotherapy courses were administered (range 1–4, mean 2.2). Pts were submitted to blood sampling previous starting of infusion, and 12, 24,48,72,96, 100, 104, 114, and 120 hours after treatment beginning. Plasma samples were stored at 0°C. Chemical analysis was perfonned using HPLC. Maximum concentration of the drug was observed at 24th hour (C24: 61.5 ± 21.9/μg/ml) while decreased pseudo-steady rate levels were reached after 70–80 hours (Css: 28.3 ± 11.5 μg/ml). Tenninal half life was 3.2 ± 0.4 hours; AVC (following trapezoidal rule) was 3654 ± 1222 mg/l. × hour. Median Clearances (total dose/AVC) was 7.14 ± 3.31/h. At the second or following cycles a relevant reduction of Tl/2 and AVC (–20% and –25%) due to enzymatic auto induction was observed. In confront with Ifosfamide administration at the same doses but in 1 hour infusion we observed that C.I. leads to a higher AUC (3650 vs. 1230) to a shorter Tl/2 (3.2 h. vs. 5.9 h.) and to a relevant increase of total clearance (7.14 vs. 3.9). This significant difference in pharmacokinetic profile can explain the different spectrum of activity between the two manners of administration. Ifosfamide, an oxazophosphorin compound, active in mesenchimal tumours has recently been used at high doses (14–18 g/sqm) in order to increase the number of responses. Continuous infusion (C.L) of Ifosfamide probably decreases toxicity and increases the therapeutic window of the drug. Bone marrow and renal toxicities seem to be modified greatly by C.L.. Aim of our study has been to characterize the pharmacokinetic drug profile during C.L high dose-fosfamide (HD-IFO). From April to December 1994, 9 patients (pts) with advanced soft tissue sarcomas, 5 pts with osteosarcomas and I pts with Ewing's sarcoma with normal liver and renal function, treated with C.I. HD-IFO (14 g/sqm. over 4 days) and Mesna contemporary infusion, entered into the study. 33 chemotherapy courses were administered (range 1–4, mean 2.2). Pts were submitted to blood sampling previous starting of infusion, and 12, 24,48,72,96, 100, 104, 114, and 120 hours after treatment beginning. Plasma samples were stored at 0°C. Chemical analysis was perfonned using HPLC. Maximum concentration of the drug was observed at 24th hour (C24: 61.5 ± 21.9/μg/ml) while decreased pseudo-steady rate levels were reached after 70–80 hours (Css: 28.3 ± 11.5 μg/ml). Tenninal half life was 3.2 ± 0.4 hours; AVC (following trapezoidal rule) was 3654 ± 1222 mg/l. × hour. Median Clearances (total dose/AVC) was 7.14 ± 3.31/h. At the second or following cycles a relevant reduction of Tl/2 and AVC (–20% and –25%) due to enzymatic auto induction was observed. In confront with Ifosfamide administration at the same doses but in 1 hour infusion we observed that C.I. leads to a higher AUC (3650 vs. 1230) to a shorter Tl/2 (3.2 h. vs. 5.9 h.) and to a relevant increase of total clearance (7.14 vs. 3.9). This significant difference in pharmacokinetic profile can explain the different spectrum of activity between the two manners of administration.

Optimal adaptive control of pharmacodynamic effects with aminoglycoside antibiotics: A required approach for the future

Many factors are considered in designing optimal drug regimens, including dose, route of administration, and the frequency and rate of administration. It is evident that the first parameter to be considered in dosage regimen determinations is the pharmacokinetics of the drug in the treated patient, or more extensively in the corresponding specific population of patients characterized by a similar pathophysiological status, e.g. neutropenics, ICU patients, subjects with renal insufficency, children, geriatrics… Therefore, over the last two decades, pharmacokinetic principles have widely, and almost exclusively influenced the optimal adaptative control of antibiotics with a small therapeutic index. The large number of available new drugs associated with medical progress, specially in considering the increase of surviving patients with severe diseases or precarious physiopathological status (e.g., neutropenia, AIDS, ICU patients…) have demonstrated the limits of this approach and pointed out the necessity of the determination of suitable parameters reflecting the in vivo efficacy. Thus, the search for pharmacodynamic parameters that can be accurately related to pharmacokinetic profiles in patients becomes a major tool. The progress in measurement of antibiotics and the additional dimension of the antibiotic's efficacy evaluation based on the analysis of the time course of the antibacterial effects, have provided the basis for the coupled evaluation of pharmacokinetics and pharmacodynamics of antibiotics, which has been largely assessed by in vivo animal models. In an attempt to propose a methodology that can provide information directly applicable to patients to be treated, we have developed a human in vivo/ex vivo model of analysis of the pharmacodynamics of antibiotics. This model has been applied to several drugs and particularly to aminoglycosides. It allows one to have a more rational evaluation of the dose-concentration-effect relations for antibiotics in man. The pharmacodynamics of aminoglycosides is characterized by a strong concentration dependent bactericidal activity and a significant post-antibiotic effect against Gram-negative bacilli. Experimental animal studies confirmed by investigations in man have shown that in vivo efficacy is enhanced by increasing the C max and the AUC of these antibiotics regardless of the possible below-MIC value of the C min. Moreover, the in vivo efficacy seems to be the same whether the total dose of aminoglycoside is given as a once a day dosing or as several doses while the toxic risk appears to be attenuated by the first dosage schedule. These data also emphasize the need for the development of models and software for optimal adaptive control including the pharmacodynamic parameters of antibiotics.

Clinical Pharmacokinetics in Patients with Spinal Cord Injuries

Although spinal cord injury is a catastrophic affliction with numerous victims and a variety of physiological manifestations, the associated disarray in physiology has yet to be systematically or comprehensively studied as a probable cause for altered pharmacokinetics. A significant increase in the volume of distribution of drugs such as the aminoglycosides (gentamicin, amikacin, tobramycin), which are highly distributed into the extracellular fluid space and minimally biotransformed, may be anticipated in patients with chronic spinal cord injury. Changes in total body clearance have also been observed for some of these medications. The influence of the pathophysiology of spinal cord injury on gastrointestinal motility appears to be reflected in an impairment in the bioavailability of drugs [theophylline, paracetamol (acetaminophen), doxycycline] which are passively absorbed and which require an intact postprandial gastric emptying to ensure efficient absorption. For theophylline, the impairment in gastrointestinal absorption appears to be directly proportional to both the magnitude of the impairment in gastric emptying and to the neurological level of the injury. Metoclopramide, a gastrointestinal prokinetic drug, has been shown to be extremely effective in normalising the impaired postprandial gastric emptying that characterises spinal cord injury. The systemic absorption of 2 antibiotics (gentamicin and cefotiam) injected into paralysed muscle is also impaired in patients with spinal cord injury, suggesting that a decrease in therapeutic efficacy attributable to this mode of administration may be anticipated. Despite the multiplicity of drugs commonly prescribed for patients with this injury, little is known about the influence of this illness on either bioavailability or postabsorptive pharmacokinetics. For drugs which are biotransformed and which have a relatively small volume of distribution (theophylline, lorazepam, ranitidine), single-dose intravenous pharmacokinetic profiles in patients with spinal cord injury are indistinguishable from the drug disposition profiles characteristic of healthy control populations. It may be inferred, then that the influence of the pathophysiology of spinal cord injury on drug disposition is greatest on those drugs which are the least biotransformed and most likely to be distributed into the increased extracellular fluid volume which is characteristic of patients with this disability.(ABSTRACT TRUNCATED AT 400 WORDS)