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Pan-PI3K inhibitor

Copanlisib

Aliqopa · COP

Pan-PI3K inhibitor · approved 2017 · 6 references

IV pan-PI3K inhibitor with reproducible transient infusion-related hypertension and hyperglycemia — a vascular/metabolic signature rather than a structural nephropathy.

Signature injury
Hypertension
Severity
Moderate
Reversibility
Reversible
Onset
Acute and infusion-bound — within hours of each dose, resolving within ~24 h.

Signature kidney injury & incidence

Hypertension — representative incidence ~29.6%.

On monotherapy (CHRONOS-1), transient on-infusion-day hypertension occurs in 29.6% all-grade (grade 3 23.9%), and hyperglycemia in 50.0% all-grade (grade 3 33.1%, grade 4 7.0%); with rituximab (CHRONOS-3) the grade 3-4 rates are higher — hypertension 40% and hyperglycemia 56%. Both peak within hours of the infusion and largely resolve by the next day. Sustained renal injury is uncommon.

Source: Dreyling et al., Am J Hematol 2020 (CHRONOS-1; 50.0% all-grade transient hyperglycemia, grade 3 33.1% — an on-target metabolic effect, not renal injury); Matasar et al., Lancet Oncol 2021 (CHRONOS-3; grade 3-4 hyperglycemia 56%, hypertension 40%)

Reported injury signatures: Hypertension.

Onset timing & rechallenge

Hyperacute (<24 h) — Infusion-bound — within hours of each dose, resolving within ~24 h.

Mechanism of kidney injury

PI3K-alpha inhibition transiently impairs endothelial nitric-oxide signaling and insulin-mediated glucose handling, producing a sharp, infusion-day spike in blood pressure and glucose. The hypertension is a hemodynamic/vascular phenomenon; the hyperglycemia is on-target insulin resistance. Both resolve as drug levels fall, so the kidney is exposed to a transient pressure and osmotic load rather than a fixed structural lesion. Severe uncontrolled hypertension or marked hyperglycemia could theoretically contribute to hemodynamic AKI.

Clinical presentation

Predictable blood-pressure rise (often peaking ~2-5 h post-infusion) and hyperglycemia on each treatment day, both typically normalizing by the following morning; symptomatic patients may report headache or flushing. Persistent renal dysfunction is unusual.

Management

Manage the acute hypertensive episode with antihypertensives and the hyperglycemia with short-acting agents/insulin as needed; both usually self-resolve before the next cycle. Optimize baseline BP and glucose between cycles. Dose-interrupt or reduce for recurrent grade 3+ events. Sustained AKI is rare and managed supportively.

Risk factors

  • Pre-existing hypertension or diabetes
  • Inadequate pre-infusion blood-pressure/glucose control
  • Concurrent agents raising BP or glucose (e.g. steroids)
  • Baseline CKD

Prevention

  • Confirm BP <140/90 before each infusion and treat hypertension proactively
  • Optimize fasting glucose before dosing
  • Hold or reduce dose for grade 3+ hypertension or hyperglycemia per label

Renal dose adjustment

No specific dose adjustment for renal impairment in labeling; hepatic metabolism predominates. Dose modification is driven by hypertension, hyperglycemia and cytopenias rather than GFR.

Dialyzability & ESKD dosing

Protein-bound IV agent given intermittently; not expected to be dialyzable, and ESKD dosing is not established.

Differential diagnosis

Distinguish the transient, predictable infusion-day BP/glucose spikes from sustained essential hypertension, from other VEGF-pathway hypertension, and from genuine structural AKI (which would persist between cycles).

Monitoring

  • Blood pressure before, during and after each infusion (treatment day)
  • Fasting glucose before each infusion; post-infusion glucose if diabetic
  • CBC each cycle

Key trials & series

  • CHRONOS-3 (Matasar, Lancet Oncol 2021) — copanlisib + rituximab, the registrational combination dataset
  • CHRONOS-1 (Dreyling, Am J Hematol 2020) — monotherapy safety quantifying the hyperglycemia/hypertension signal

Clinical pearls

  • Hyperglycemia and hypertension here are time-locked to the infusion and transient — a vascular/metabolic signature, not a fixed nephropathy.
  • Get BP under control before each dose; the infusion-day spike is anticipated and dose-limiting.
  • Persistent (between-cycle) renal dysfunction should prompt a search for an alternative cause.

Anticancer mechanism

Intravenous pan-class-I PI3K inhibitor with predominant activity against the alpha and delta isoforms. Intermittent IV dosing blocks PI3K/AKT signaling in follicular and other indolent B-cell lymphomas.

Note

The renal-relevant toxicities (hypertension, hyperglycemia) are transient and infusion-bound rather than a direct structural kidney lesion; the cited incidence figures are real and quantified.

Guidelines & consensus

Each recommendation below is this atlas's faithful summary of the source, not a quotation from it — follow the PubMed link for the wording the society published. Summaries may be superseded; consult the current full text and individualize to the patient.

  • ADQI (2026) — The nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupProvides expert-based statements (modified Delphi) on preventing and managing cisplatin/platinum-associated AKI, including isotonic IV hydration, attention to volume status and concomitant nephrotoxins, and incorporates evidence that IV magnesium supplementation may reduce cisplatin-associated AKI; emphasizes risk stratification and standardized AKI definitions.Nat Rev Nephrol · PMID 41361704
  • SIRM (2022) — SIRM-SIN-AIOM: appropriateness criteria for evaluation and prevention of renal damage in the patient undergoing contrast medium examinations-consensus statements from Italian College of Radiology (SIRM), Italian College of Nephrology (SIN) and Italian Association of Medical Oncology (AIOM)Recommends eGFR-based renal risk assessment and pre/post-contrast isotonic saline or sodium bicarbonate hydration; advises maintaining a 5-7 day interval between iodinated contrast administration and cisplatin in cancer patients to reduce additive nephrotoxicity.Radiol Med · PMID 35303246
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerIdentifies platinum compounds (especially cisplatin) as leading cytotoxic causes of acute tubular injury, AKI, and electrolyte/magnesium wasting; calls for interdisciplinary onco-nephrology care, accurate GFR estimation, and individualized drug dosing in patients with reduced kidney function.Kidney Int · PMID 33126977
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationAddresses chemotherapy-associated AKI/CKD in hematologic cancer, GFR estimation and chemotherapy dosing in patients with reduced kidney function, and management priorities and research gaps for onco-nephrology care.Kidney Int · PMID 33276867
  • ADDIKD (2025) — Integrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceProvides GRADE-based, drug-specific dose-adjustment recommendations for anticancer agents in kidney dysfunction (illustrated for methotrexate, cisplatin, carboplatin and nivolumab); the recommendations build on Part 1's standardised CKD-EPI eGFR assessment rather than Cockcroft-Gault creatinine clearance.EClinicalMedicine · PMID 40290844
  • ADDIKD (2025) — Aligning kidney function assessment in patients with cancer to global practices in internal medicineThree consensus recommendations: assess kidney function by GFR (measured GFR or CKD-EPI eGFR), classify it using KDIGO categories, and use this uniform approach to dose anticancer drugs — moving cancer medicine away from Cockcroft-Gault estimated creatinine clearance.EClinicalMedicine · PMID 40290845
  • ADDIKD (2025) — A methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEstablishes that, where RCT evidence is lacking, anticancer drug dosing recommendations in kidney dysfunction should be derived by critically appraising observational literature via GRADE combined with structured international multidisciplinary consensus voting.EClinicalMedicine · PMID 40290846
  • KDIGO (2013) — Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Defines/stages AKI by serum creatinine and urine output; emphasizes avoiding nephrotoxins, maintaining euvolemia/perfusion, dose-adjusting drugs to kidney function, and monitoring high-risk patients — the framework applied to nephrotoxic anti-cancer agents.Crit Care · PMID 23394211
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknownsEvaluate and risk-stratify CKD, manage to delay progression and its complications, and practise explicit medication management and drug stewardship — the framework the atlas's G1–G5 eGFR banding and every renal dose-adjustment recommendation sit inside. Because the guideline excludes dialysis and transplant recipients by its own statement of scope, its recommendations do not carry to those settings, where this atlas's dialyzability and post-transplant guidance rests on other sources.Kidney Int · PMID 38519239
  • KDIGO (2021) — Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesProvides the staging/treatment framework for drug-associated glomerular lesions (e.g., bisphosphonate- and interferon-related collapsing FSGS, VEGF-inhibitor podocytopathy/proteinuria), including immunosuppression and supportive RAAS-blockade strategies.Kidney Int · PMID 34556300
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisUpdates immunosuppressive induction (rituximab/cyclophosphamide), incorporates avacopan and lower-dose or glucocorticoid-sparing regimens — the management framework for drug- and checkpoint-inhibitor-associated ANCA/pauci-immune glomerulonephritis.Kidney Int · PMID 38388147
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisUpdates first-line lupus nephritis therapy to combination immunosuppression with the addition of belimumab or a calcineurin inhibitor (voclosporin) — informs management of immune-complex/lupus-like glomerulonephritis encountered with immunotherapy.Kidney Int · PMID 38182299
  • KDIGO (2025) — Executive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Encourages liberal kidney biopsy and stricter proteinuria control (<0.5 g/d, ideally <0.3 g/d) with RAAS blockers, SGLT2 inhibitors, and targeted-release budesonide — the framework for IgA-dominant glomerular lesions, including those triggered by immune-modulating cancer therapy.Kidney Int · PMID 40975525

References

6 peer-reviewed references. Citation metadata via PubMed / NLM.

  1. 1.Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial.Matasar MJ et al. · Lancet Oncol · 2021 · PMID 33848462
  2. 2.Long-term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2-year follow-up of the CHRONOS-1 study.Dreyling M et al. · Am J Hematol · 2020 · PMID 31868245
  3. 3.Copanlisib: An Intravenous Phosphatidylinositol 3-Kinase (PI3K) Inhibitor for the Treatment of Relapsed Follicular Lymphoma.Eltantawy A et al. · Ann Pharmacother · 2019 · PMID 30813760
  4. 4.Phase I dose-escalation study of copanlisib in combination with gemcitabine or cisplatin plus gemcitabine in patients with advanced cancer.Kim RD et al. · Br J Cancer · 2018 · PMID 29348486
  5. 5.Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL.Bojarczuk K et al. · Blood · 2018 · PMID 30322870
  6. 6.A preclinical evaluation of the PI3K alpha/delta dominant inhibitor BAY 80-6946 in HER2-positive breast cancer models with acquired resistance to the HER2-targeted therapies trastuzumab and lapatinib.Elster N et al. · Breast Cancer Res Treat · 2014 · PMID 25528022
Educational monograph from NephTox (nephtox.com). Not medical advice — verify against current guidelines before any clinical decision.