Characterizing the relationship between the pharmacokinetics (PK, concentration vs. time) and pharmacodynamics (PD, effect vs. time) is an important tool in the discovery and development of new drugs ...in the pharmaceutical industry. The purpose of this publication is to serve as a guide for drug discovery scientists toward optimal design and conduct of PK/PD studies in the research phase. This review is a result of the collaborative efforts of DMPK scientists from various Metabolism and Pharmacokinetic (MAP) departments of the global organization Novartis Institute of Biomedical Research (NIBR). We recommend that PK/PD strategies be implemented in early research phases of drug discovery projects to enable successful transition to drug development. Effective PK/PD study design, analysis, and interpretation can help scientists elucidate the relationship between PK and PD, understand the mechanism of drug action, and identify PK properties for further improvement and optimal compound design. Additionally, PK/PD modeling can help increase the translation of in vitro compound potency to the in vivo setting, reduce the number of in vivo animal studies, and improve translation of findings from preclinical species into the clinical setting. This review focuses on three important elements of successful PK/PD studies, namely partnership among key scientists involved in the study execution; parameters that influence study designs; and data analysis and interpretation. Specific examples and case studies are highlighted to help demonstrate key points for consideration. The intent is to provide a broad PK/PD foundation for colleagues in the pharmaceutical industry and serve as a tool to promote appropriate discussions on early research project teams with key scientists involved in PK/PD studies.
To identify the effects of anti-angiogenic therapy in neovascular age-related macular degeneration (AMD) in respect to morphologic type and time course and to identify prognostic factors for visual ...outcome on the basis of standardized optical coherence tomography (OCT) analysis.
Subanalysis of a prospective, 12-month, multicenter, phase IIIb trial (Efficacy and Safety of Ranibizumab in Patients with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration EXCITE).
A total of 353 treatment-naïve patients with subfoveal choroidal neovascularization (CNV) receiving quarterly or monthly ranibizumab therapy.
Patients were randomized to receive 0.3 mg quarterly, 0.5 mg quarterly, or 0.3 mg monthly doses of ranibizumab. Treatment comprised a loading phase of 3 consecutive monthly injections followed by a 9-month maintenance phase of monthly or quarterly injections. Best-corrected visual acuity (BCVA) was measured using the Early Treatment Diabetic Retinopathy Study protocol, and retinal morphology was assessed by Stratus OCT (Carl Zeiss Meditec, Dublin, CA). Imaging data were evaluated by certified examiners of the Vienna Reading Center using a standardized protocol.
The BCVA was measured using ETDRS charts and retinal morphology was assessed by OCT.
During the loading phase, there was a significant correlation between a reduction in central retinal thickness and an increase in BCVA (P < 0.001), which decreased during the maintenance phase in all treatment arms. The proportion of patients showing retinal morphologic changes, such as intraretinal cysts (IRCs), subretinal fluid (SRF), and pigment epithelial detachments (PEDs), decreased significantly in all groups (P < 0.001), more intensively in the 0.5 mg quarterly than in both 0.3 mg groups. Intraretinal cysts resolved most rapidly followed by SRF, whereas PED decreased at a slower rate and intensity. Patients with IRC at baseline had lower BCVA levels that remained lower over the entire study period, whereas recurrence of IRC during follow-up showed no additional negative effect on function. Baseline SRF had no effect on visual recovery; however, recurrence of SRF during follow-up showed a tendency for an additional negative effect on function (P = 0.06). Baseline PED showed a negative influence on visual outcome only in combination with IRC and SRF.
There is a distinct response pattern and time course of morphologic parameters associated with anti-vascular endothelial growth factor therapy in neovascular AMD. Specific alterations, such as IRC, SRF, and PED, as baseline or follow-up features are significantly influencing the potential for visual gain.
In discussion with Lukas Meier from the Swiss Tropical and Public Health Institute (Swiss TPH), Lutz Hegemann, Head of Novartis Global Health and Sustainability and Marcel Tanner, President of the ...Swiss Academies of Arts and Sciences, give their opinions on the changes that occurred in drug discovery and development for poverty-related diseases over the past 30 years. They emphasise the power of public–private partnerships and provide their points of views on what needs to be done in the future to ensure that the poorest of the poor also have access to important therapies
Patients ≥ 70 years of age with acute myeloid leukemia (AML) have a poor prognosis. Recent studies suggested that intensive AML-type therapy is tolerated and may benefit most. We analyzed 446 ...patients ≥ 70 years of age with AML (≥ 20% blasts) treated with cytarabine-based intensive chemotherapy between 1990 and 2008 to identify risk groups for high induction (8-week) mortality. Excluding patients with favorable karyotypes, the overall complete response rate was 45%, 4-week mortality was 26%, and 8-week mortality was 36%. The median survival was 4.6 months, and the 1-year survival rate was 28%. Survival was similar among patients treated before 2000 and since 2000. A multivariate analysis of prognostic factors for 8-week mortality identified the following to be independently adverse: age ≥ 80 years, complex karyotypes, (≥ 3 abnormalities), poor performance (2-4 Eastern Cooperative Oncology Group), and elevated creatinine > 1.3 mg/dL. Patients with none (28%), 1 (40%), 2 (23%), or ≥ 3 factors (9%) had estimated 8-week mortality rates of 16%, 31%, 55%, and 71% respectively. The 8-week mortality model also predicted for differences in complete response and survival rates. In summary, the prognosis of most patients (72%) ≥ 70 years of age with AML is poor with intensive chemotherapy (8-week mortality ≥ 30%; median survival < 6 months).
Refunds If a Drug Doesn’t Work Robbins, Richard; Kummet, Thomas
Southwest journal of pulmonary & critical care,
10/2021, Volume:
23, Issue:
4
Journal Article
Open access
No abstract available. Article truncated after 150 words. One aspect of the high cost of healthcare is the cost of new drugs. Cancer drugs have received much of the attention because of their ...extremely high price (1). For example, crizotinib, used to treat non-small cell lung cancer (NSCLC), costs $19,144 for each month's supply. Pfizer, the manufacturer of crizotinib, has just announced that they are offering a refund if its drug "doesn't work" (2). If crizotinib use is discontinued and documentation of ineffectiveness is provided, Pfizer will refund the out-of-pocket amount that was paid for up to the first three bottles (30-day supply) of crizotinib, up to a maximum of $19,144 for each month's supply, or a total of $57,432. Of course, the cost of care includes more than just a single drug and can be much higher and Pfizer is reimbursing only the drug cost. Although Pfizer claims that its pilot program is a first in the …
Summary
Background Imatinib mesylate is a potent inhibitor of platelet‐derived growth factor and transforming growth factor‐β signalling pathways which may play a role in systemic sclerosis ...(SSc)‐associated skin changes.
Objectives We aimed primarily at assessing the efficacy of imatinib mesylate in scleroderma skin fibrosis.
Methods We performed a phase II double‐blinded trial on patients with scleroderma with either morphoea involving > 20% of body surface area or SSc with extensive skin involvement: modified Rodnan Skin Score (mRSS) ≥ 20/51. Each patient was randomized to receive either imatinib mesylate 400 mg or placebo daily for a total of 6 months, and then was followed up 6 months after therapy discontinuation. Skin fibrosis was assessed by mRSS and measurement of the dermal thickness using skin biopsies performed at inclusion and at 6 months of treatment. In addition, quality of life (Dermatology Life Quality Index and modified Health Assessment Questionnaire for Scleroderma) was recorded at each visit, and pulmonary function before and after intervention.
Results Twenty‐eight patients were included in the study with a mean age of 48·9 years (range 30–71): 25 had a diagnosis of a SSc and three of diffuse cutaneous scleroderma. Demographic data, frequency of organ involvement of SSc and mRSS were comparable between groups. At 6 months, the proportion of variation of mRSS from inclusion was not statistically significantly different between the two groups (median +0·10 in imatinib group vs. −0·16 in placebo group, P = 0·098). Similarly, changes in dermal thickness, quality of life and diffusion capacity for carbon monoxide were not significantly different between groups.
Conclusions This study failed to demonstrate the efficacy of imatinib 400 mg daily to improve skin fibrosis of diffuse scleroderma after 6 months of treatment based on validated outcome measurements.
ObjectivesGout-associated cardiovascular (CV) risk relates to comorbidities and crystal-led inflammation. The aim was to estimate the CV risk by prediction tools in new patients with gout and to ...assess whether ultrasonographic carotid changes are present in patients without high CV risk.MethodsCross-sectional study. Consecutive new patients with crystal-proven gout underwent a structured CV consultation, including CV events, risk factors and two risk prediction tools—the Systematic COronary Evaluation (SCORE) and the Framingham Heart Study (FHS). CV risk was stratified according to current European guidelines. Carotid ultrasound (cUS) was performed in patients with less than very high CV risk. The presence of carotid plaques was studied depending on the SCORE and FHS by the area under the curve (AUC) of receiver operating curves.Results237 new patients with gout were recruited. CV stratification by scores showed a predominance of very high (95 patients, 40.1%) and moderate (72 patients, 30.5%) risk levels. cUS was performed in 142 patients, finding atheroma plaques in 66 (46.5%, 95% CI 37.8 to 54.2). Following cUS findings, patients classified as very high risk increased from 40.1% up to 67.9% (161/237 patients). SCORE and FHS predicted moderately (AUC 0.711 and 0.683, respectively) the presence of atheroma plaques at cUS.ConclusionsThe majority of patients presenting with gout may be at very high CV risk, indicating the need for initiating optimal prevention strategies at this stage. Risk prediction tools appear to underestimate the presence of carotid plaque in patients with gout.
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