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Tyrosine kinase inhibitor (TKI) therapy discontinuation practice in patients with chronic myeloid leukemia chronic phase (CML-CP) was assessed in real-world practice prior to the release of recommendations on discontinuation. Data were collected from US oncologists/hematologists (through web-based physician survey and patient chart review) on TKI therapy discontinuation practice including monitoring, adequate response for discontinuation, relapse, and symptoms following discontinuation. From the physician survey, 34% of oncologists/hematologists attempted discontinuation, with two-thirds doing so outside of a trial. From the chart review, TKI therapy was discontinued in 3.4% of patients after they achieved an adequate response with the intention to remain CML-therapy-free until disease relapse. Among these patients, 21% relapsed and 17% had symptoms following discontinuation. There was a lack of consensus on the definition of adequate response suggesting that discontinuation was attempted without clear guidelines and under suboptimal conditions underscoring the need for physician education regarding guidelines for TKI therapy discontinuation.

Background: Tisagenlecleucel (Kymriah) is an autologous CD19-directed CAR-T-cell therapy, approved in Aug-2017 for treating children and young adults with relapsed/refractory (r/r) acute lymphoblastic leukemia and in May-2018 for treating adults with r/r diffuse large B-cell lymphoma. Post-approval, a key goal has been to upscale and continuously improve manufacturing success and turnaround time in the commercial settings to meet the needs of a global patient population. Here we report accrued experience from our 4-year journey of optimizing the commercial tisagenlecleucel manufacturing process at the US site (Morris Plains, NJ), for faster and successful delivery to patients in the US. Methods: As reported previously, the tisagenlecleucel manufacturing process includes leukapheresis of the patient's peripheral blood mononuclear cells, enrichment and activation of T cells, transduction of the lentiviral vector containing the anti-CD19 CAR transgene, activation with anti-CD3/CD28 antibody-coated beads, expansion in cell culture, washing, and formulation of the viable cells into a cryoformulation medium. The final product is then cryopreserved, shipped back to the treatment center and infused to patients (Tyagarajan, 2020). Use of cryopreserved leukapheresis material as the starting point in commercial manufacturing is unique to tisagenlecleucel; this allows flexibility in terms of scheduling leukapheresis when a patient's health is optimal to provide T cells, and also helps offset logistical challenges (Tyagarajan, 2019). Results: As of Jun-2021, tisagenlecleucel has been manufactured for >5000 patients worldwide, enabled by Novartis's significantly increased global manufacturing footprint at six sites strategically located across six countries (US, France, Switzerland, Germany, Japan and Australia) and a global treatment network of >340 certified centers, including 127 centers in the US. Specifically for the US manufacturing site, between Dec-2020 and Jun-2021, 376 patients in the US had starting material available for manufacturing. Overall, the manufactured product was available for shipment for 98% of patients (shipping success rate [SSR]). The commercial manufacturing success rate (MSR) was 96%, with an out-of-specification (OOS) rate of Immediate manufacturing capability without waiting time was available on receipt of all apheresis starting materials. The median time from start of manufacturing to shipping was 20 days. As is evident, the COVID-19 pandemic did not appear to have significantly affected the success rate or manufacturing turnaround time. These latest success metrics, reflecting significant improvements from 2018 to 2021 in MSR (69% to 96%), SSR (93% to 98%), and overall OOS rate (26% to 2%) including viability OOS rate (from 25% to 0%), are a result of upscaling the manufacturing capabilities, enhancements with hospitals focusing on optimizing apheresis collection and cryopreservation procedures, and continuous evaluation and improvement of the manufacturing process since tisagenlecleucel was first launched (Figure). Two key process and analytical improvements that were considered to have improved robustness of manufacturing and testing processes, reduced OOS rates, and minimized variability in turnaround time were introduced towards the end of 2020. Firstly, a simplified sample preparation procedure for final product cell count and viability measurement, which is more reflective of final product at infusion. Secondly, an alternate serum source (5% plasma-derived human AB serum [PD hABs]) which further improves process robustness with a trend towards improved growth and higher peak cell counts. Conclusions: Tisagenlecleucel's current global commercial manufacturing footprint and treatment network are well-positioned to meet anticipated future increase in demand for CAR-T therapies. Recent process improvements have significantly increased the MSR (to 96%) and SSR (to 98%), and immediate product availability for patients in need of CAR-T cells. Ongoing and upcoming process improvements are anticipated to further reduce the throughput time, thus allowing more patients faster access to CAR-T therapy. Figure 1 Figure 1. Disclosures Rodrigues: Novartis: Current Employment. Duran: Novartis: Current Employment. Eschgfaeller: Novartis: Current Employment. Kuzan: Novartis: Current Employment. Habucky: Novartis: Current Employment.

Tyrosine kinase inhibitors (TKI) have been demonstrated to prolong survival in patients with chronic myeloid leukemia (CML). However, TKIs may be associated with an increased risk of infections. This study compared healthcare resource utilization (HRU) and costs among patients with CML receiving dasatinib or nilotinib, with a focus on infection-related economic outcomes. Two large administrative databases were used to identify adult patients newly diagnosed with CML who initiated dasatinib or nilotinib as first- (1L) or second-line (2L) therapy and were classified into the following 1L (dasatinib 1L/nilotinib 1L cohorts) or 2L (dasatinib 2L/nilotinib 2L) cohorts based on the initiated 1L/2L TKI therapy. Infection-related HRU and healthcare costs were compared between cohorts, separately for 1L and 2L. Cohorts included 1156 patients in the dasatinib 1L and 677 patients in the nilotinib 1L cohorts, 322 patients in the dasatinib 2L, and 207 in the nilotinib 2L cohorts. In 1L and 2L, infection-related HRU was higher for dasatinib than nilotinib cohorts. Infection-related inpatient (IP) days constituted a larger proportion of all-cause IP days in the 1L/2L dasatinib than 1L/2L nilotinib cohorts (dasatinib 1L/2L: 53%/58%; nilotinib 1L/2L: 50%/46%). Compared to the nilotinib cohort, the dasatinib cohort had higher all-cause total costs per patient per year by US$17,901 in 1L and $28,625 in 2L. Of the total cost difference, infection-related were $6048 (34%) in 1L and $28,192 (99%) in 2L, largely driven by IP cost differences (1L/2L: 96%/98%). Dasatinib was associated with higher HRU and healthcare costs compared to nilotinib, particularly related to infections. Novartis Pharmaceutical Corporation.

Cyclosporin is an essential component of the antirejection drug protocol used in the long term management of paediatric organ transplant recipients. This article looks at the pharmacokinetics of cyclosporin in paediatric kidney, heart, liver and bone marrow transplant recipients and critically evaluates its relationship to pharmacokinetic data in adult transplant recipients. There are limited data on the pharmacokinetics of cyclosporin in paediatric transplant recipients (14 publications provide the database) as compared with the adult transplant population. Study design, analytical methodology and age ranges of the individuals differ between studies, making comparative interpretation of pharmacokinetic data difficult. However, significant trends are noteworthy and these may influence dose administration guidelines and therapeutic monitoring standards for cyclosporin in the paediatric organ transplant recipient. The bioavailability of the oral formulations of cyclosporin is highly variable as with the adult population, but there appears to be a correlation between cyclosporin bioavailability and age with both the traditional oral formulation (Sandimmun) and the new microemulsion formulation (Neoral) in young liver transplant patients. Bowel length, presystemic metabolism in the gut wall, type of transplant and time since transplant are contributing factors in the variation of bioavailability patterns in paediatric transplant patients. The volume of distribution of cyclosporin does not appear to differ between paediatric and adult transplant recipients, but systemic clearance is comparatively higher in the paediatric population. In general, paediatric patients require higher doses of cyclosporin to achieve target blood concentrations of the drug which are equivalent to the values used in the adult population. Younger patients (less than 8 years of age) may be managed more effectively with a 3 times daily administration schedule rather than the twice daily schedule which is universally used for cyclosporin in the transplant population. The comparatively higher doses and more frequent administration schedule used in paediatric transplant recipients are the consequence of age-related differences in bioavailability and the possibility of increased metabolic clearance of the drug in younger patients.

To define the pharmacokinetics and pharmacodynamics of ritodrine after intramuscular injection, we administered 5 or 10 mg ritodrine into the gluteus or deltoid muscles of 12 pregnant volunteers. Six women received 5 mg and six received 10 mg into each muscle group on different days. We withdrew blood samples before and 12 times in the 6 hours after ritodrine injection. Blood pressure and heart rate were recorded at each time. Ritodrine was measured by high-performance liquid chromatography. Peak ritodrine concentrations (mean +/- SD) after a single 5 mg injection in the deltoid or gluteus were 38 +/- 13 and 26 +/- 8 ng/ml, respectively. After a 10 mg dose in the deltoid or gluteus, peak concentrations were 59 +/- 30 and 47 +/- 22 ng/ml, respectively. Although higher, the peak plasma concentrations after injections into the deltoid were not significantly greater than those after injection into the gluteus. None of the pharmacokinetic parameters differed according to dose or injection site. The pharmacodynamic effects of ritodrine were unaffected by injection site, but ritodrine caused a dose-related increase in heart rate and systolic blood pressure and a dose-related decrease in diastolic blood pressure. After a 10 mg injection, the maximal changes in heart rate, systolic, and diastolic blood pressure were 22%, 10%, and 19%, respectively. However, mean blood pressure was not altered by either the 5 or 10 mg dose. These findings indicate that there are few differences in pharmacokinetic parameters between deltoid and gluteal injection of ritodrine. The single intramuscular injection of 5 or 10 mg ritodrine results in labor-inhibiting concentrations with clinically insignificant cardiovascular effects.

Diseases of the liver, kidney and heart influence the pharmacokinetics of several drugs. Organ transplantation is an accepted therapeutic option for the treatment of several disease states associated with these organs. Recently, there has been an increase in both graft and patient survival after transplantation of the liver, heart, kidney and bone marrow. Such patients normally receive a wide range of drugs, and optimisation of drug therapy requires a thorough understanding of the pharmacokinetics and pharmacodynamics of these drugs in transplant patients. However, only limited studies have been carried out to characterise drug kinetics in these situations. Available information indicates that drug kinetics cannot be considered normal in transplant patients. Drug absorption generally appears to be similar to that in healthy subjects. The plasma protein binding of drugs that primarily bind to albumin increases after transplantation, but remains lower than that observed in healthy subjects. While the binding of certain basic drugs may increase after transplantation due to an increase in the concentration of alpha 1-acid glycoprotein, a lower albumin concentration may mask this effect. Oxidative and conjugative metabolism as measured by the kinetics of antipyrine (phenazone) and paracetamol (acetaminophen) is normal, while the metabolism of steroids may be impaired. Serum creatinine does not appear to be a good indicator of the functional status of the kidney in transplant patients. It is also important to realise that there will be time-dependent changes in several kinetic parameters of drugs due to improvement in the physiological function from that associated with the disease state to that of the normal state. Individualisation and close monitoring of drug therapy is necessary in transplant patients.