Nivolumab exposure–response analysis for adjuvant treatment of melanoma supporting a change in posology

Sanghavi, Kinjal; Vuppala, Pradeep K.; Ivaturi, Vijay; Hamuro, Lora; Roy, Amit; Suryawanshi, Satyendra

doi:10.1002/psp4.12642

Cited by 4 publications

(4 citation statements)

References 24 publications

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“…Similarly, new advances in drug development include the introduction of improved drug posology [67][68][69], different routes of administration [70,71], new improved formulations, nanomedicines and other drug carriers, and drug combinations [71][72][73][74]. In the meantime, it should be noted that millions of patients choose to be treated in alternative medicine clinics using non-conventional treatments including a wide range of folk medicines, nutraceuticals and alternative medicinal drugs and combinations [75][76][77][78][79].…”

Section: Introductionmentioning

confidence: 99%

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

Kontoghiorghes

2023

IJMS

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The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols could ideally be designed in all diseases including for millions of patients affected by excess iron deposition (EID) toxicity based on personalised medicine parameters, as well as many variations and limitations. EID is an adverse prognostic factor for all diseases and especially for millions of chronically red-blood-cell-transfused patients. Differences in iron chelation therapy posology cause disappointing results in neurodegenerative diseases at low doses, but lifesaving outcomes in thalassemia major (TM) when using higher doses. In particular, the transformation of TM from a fatal to a chronic disease has been achieved using effective doses of oral deferiprone (L1), which improved compliance and cleared excess toxic iron from the heart associated with increased mortality in TM. Furthermore, effective L1 and L1/deferoxamine combination posology resulted in the complete elimination of EID and the maintenance of normal iron store levels in TM. The selection of effective chelation protocols has been monitored by MRI T2* diagnosis for EID levels in different organs. Millions of other iron-loaded patients with sickle cell anemia, myelodysplasia and haemopoietic stem cell transplantation, or non-iron-loaded categories with EID in different organs could also benefit from such chelation therapy advances. Drawbacks of chelation therapy include drug toxicity in some patients and also the wide use of suboptimal chelation protocols, resulting in ineffective therapies. Drug metabolic effects, and interactions with other metals, drugs and dietary molecules also affected iron chelation therapy. Drug selection and the identification of effective or optimal dose protocols are essential for positive therapeutic outcomes in the use of chelating drugs in TM and other iron-loaded and non-iron-loaded conditions, as well as general iron toxicity.

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Section: Introductionmentioning

confidence: 99%

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

Kontoghiorghes

2023

IJMS

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“…13 Data from these studies, as well as those in adult patients treated in advMEL and adjMEL settings, where pharmacokinetic (PK) and exposure-response (E-R) efficacy and safety relationships were characterized, were combined to support dosing recommendations for nivolumab alone and/or combined with ipilimumab in adolescents with MEL. [18][19][20][21][22][23][24] A greater understanding of the exposure-driven safety risk in adolescents is crucial to ensure the safe administration of these agents, particularly because of the overlapping toxicities of nivolumab and ipilimumab and the potentially higher exposure of these agents in adolescents (unpublished data). Previous use of population PK (PopPK) and E-R modeling to support posology changes in adults for nivolumab and nivolumab plus ipilimumab have been conducted.…”

Section: Introductionmentioning

confidence: 99%

“…However, a trend toward higher toxicity was noted in a smaller proportion of patients from the same study who received the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) approved dosing regimen for adults with MEL 13 . Data from these studies, as well as those in adult patients treated in advMEL and adjMEL settings, where pharmacokinetic (PK) and exposure–response (E–R) efficacy and safety relationships were characterized, were combined to support dosing recommendations for nivolumab alone and/or combined with ipilimumab in adolescents with MEL 18–24 …”

Section: Introductionmentioning

confidence: 99%

“… 13 Data from these studies, as well as those in adult patients treated in advMEL and adjMEL settings, where pharmacokinetic (PK) and exposure–response (E–R) efficacy and safety relationships were characterized, were combined to support dosing recommendations for nivolumab alone and/or combined with ipilimumab in adolescents with MEL. 18 , 19 , 20 , 21 , 22 , 23 , 24 …”

Section: Introductionmentioning

confidence: 99%

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Pediatric model‐based dose optimization using a pooled exposure–response safety analysis for nivolumab and nivolumab plus ipilimumab combination in melanoma

Du,

Zhao,

et al. 2023

CPT Pharmacom & Syst Pharma

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An exposure–response (E‐R) safety analysis was conducted across adult and pediatric (<18 years) studies to evaluate the potential impact of higher nivolumab and/or ipilimumab exposures in adolescents (≥12 to <18 years ) versus adults with melanoma using the approved adult dosing regimens for nivolumab alone or in combination with ipilimumab. Data from 3507 patients across 15 studies were used to examine the relationship between nivolumab–ipilimumab daily average exposure (Cavg) and time to grade 2+ immune‐mediated adverse events (gr2+ IMAEs). Results from the E‐R safety model showed ipilimumab, but not nivolumab, exposure to be a statistically significant predictor of gr2+ IMAEs. Significant covariates included sex (41% higher risk for women than men), line of therapy (19% higher for first‐line than later‐line), and treatment setting (26% lower for adjuvant than advanced melanoma). Younger age and lower body weight (BW) were each associated with a lower risk of gr2+ IMAEs (hazard ratio, 0.830 for 15‐year‐olds versus 60‐year‐olds and 0.84 for BW 52 kg versus 75 kg). For adolescents with melanoma treated with nivolumab in the advanced or adjuvant settings, these results are supportive of nivolumab flat dosing regimens for adolescents ≥40 kg and BW‐based dosing for adolescents <40 kg. These results also support adult weight‐based dosing regimens for nivolumab plus ipilimumab in adolescents with advanced melanoma. This analysis suggests that although higher exposures are predicted in adolescents with lower weight compared with adults, there is no predicted immune‐mediated safety risk when treated with the approved adult dosing of nivolumab with/without ipilimumab.

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Model‐based population pharmacokinetic and exposure response analyses for safety and efficacy of nivolumab as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer

Zhao,

Tsujimoto,

Ide

et al. 2024

Brit J Clinical Pharma

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AimsNivolumab is approved as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer (EC/GEJC) based on results from the pivotal CheckMate 577 trial. We present a model‐based clinical pharmacology profiling and benefit–risk assessment of nivolumab as adjuvant treatment in subjects with resected EC/GEJC supporting a less frequent dosing regimen.MethodsPopulation pharmacokinetic (popPK) analysis was conducted to characterize nivolumab pharmacokinetics (PK) using clinical data from 1493 subjects from seven monotherapy clinical studies across multiple solid tumours. The exposure‐response (E‐R) analyses included data from 756 patients from CheckMate 577. E‐R relationships for efficacy and safety were characterized by evaluating the relationship between nivolumab exposure and disease‐free survival (DFS) for efficacy; and time to first occurrence of Grade ≥2 immune‐mediated adverse events (Gr2 + IMAEs) for safety.ResultsNivolumab exposure was found to be associated with both DFS and risk of Gr2 + IMAEs. However, the hazard ratios (HRs) (95% confidence interval [CI]) at the 5th and 95th percentiles of nivolumab exposure were similar for DFS and Gr2 + IMAEs, indicating flat E‐R relationships within the exposure range produced by the studied regimen. Model‐predicted probability of DFS and Gr2 + IMAEs were similar between the two regimens of 240 mg every 2 weeks or 480 mg every 4 weeks for 16 weeks followed by 480 mg Q4W up to 1 year.ConclusionsThe analyses demonstrated a flat E‐R relationship over the range of exposures produced by the studied regimen and supported the approval of an alternative dosing regimen with less frequent dosing in patients with adjuvant EC/GEJC.

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Nivolumab exposure–response analysis for adjuvant treatment of melanoma supporting a change in posology

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 4 publications

References 24 publications

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

Drug Selection and Posology, Optimal Therapies and Risk/Benefit Assessment in Medicine: The Paradigm of Iron-Chelating Drugs

Pediatric model‐based dose optimization using a pooled exposure–response safety analysis for nivolumab and nivolumab plus ipilimumab combination in melanoma

Model‐based population pharmacokinetic and exposure response analyses for safety and efficacy of nivolumab as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer

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