Rate of drug concentration rise alters hemodynamic responses and mortality risk in coronary heart disease patients

Photo by National Cancer Institute / Unsplash

medRxiv Published June 4, 2026 Medically reviewed June 4, 2026 Study authors: Kleinbloesem, C. H.; Braal, C. L. DOI ↗ By Dr. Julia Lee, PhD · Oncology, Genomics & Drug Development

Key Takeaway

Note that rate of concentration rise alters hemodynamic responses and mortality risk in coronary heart disease.

This narrative review and theoretical framework examines rate-dependent pharmacology across multiple domains. The scope includes coronary heart disease patients and a CAR-T cohort, analyzing interventions such as rate of rise of drug concentration and aggressive hemoglobin correction. The review synthesizes findings on haemodynamic responses to nifedipine, which diverge depending solely on the rate of rise. It also reports a dose-related mortality signal observed in approximately 8350 patients. In the CAR-T cohort, severe CRS was predicted by high-risk classification using ferritin and D-dimer velocity thresholds, showing 100% sensitivity in safety rule-out mode and 91.1% sensitivity with 93.6% specificity in Youden-optimised mode. The hazard ratio for aggressive hemoglobin correction was 1.34 with a 95% CI of 1.03 to 1.74 in 1432 patients. A dose-rate effectiveness factor of 1.5 to 2.0 was reported. The kinetic lead time before clinical decompensation ranged from 3 to 7 days. The authors acknowledge that this meta-analysis was itself debated. Biological tolerability is described as three-dimensional, unified by HARL. The review concludes that MTDyn, which specifies target level and allowable rate of change, should supplement conventional dose-response assessment.

Study Details

Study typeMeta analysis

Sample sizen = 8

EvidenceLevel 1

PublishedJun 2026

View Original Abstract ↓

Background Classical pharmacokinetic-pharmacodynamic (PK/PD) theory models exposure-effect in two dimensions: magnitude and time. Rate-dependent toxicity has been documented across therapeutic domains but never formalised as a conserved biological constraint. Methods We developed the Human Adaptive Rate Limit (HARL) framework, formalising the maximum tolerable velocity as |dS/dt|_max = sigma_max / tau. We validated HARL across five domains using published trial data and a reanalysis of the longitudinal biomarker data from the 202-patient CAR-T cohort of Wei et al (2023). An 8-ODE quantitative systems pharmacology model guided biomarker selection. Early biomarker velocities (maximum positive slope within days 0-5) were computed for ferritin and D-dimer. Patients were classified as high-risk only if both velocities exceeded their thresholds (dual-velocity classifier). Thresholds were identified by grid-search optimisation of the Youden index and assessed by leave-one-out cross-validation. Findings A prospective crossover study (Kleinbloesem 1987, n=8) demonstrated that matched steady-state nifedipine concentrations produce divergent haemodynamic responses depending solely on rate of rise, anticipating the dose-related mortality signal subsequently reported across ~8350 patients with coronary heart disease (Furberg 1995), a meta-analysis that was itself debated. Convergent evidence spans haematology (CHOIR, 1432 patients, hazard ratio [HR] 1.34 [1.03-1.74] for aggressive Hb correction), radiation (dose-rate effectiveness factor [DDREF] 1.5-2.0), and infusion pharmacology. In the CAR-T cohort, high-risk classification (ferritin >232 ng/mL per day AND D-dimer >1.21 mg/L per day) predicted severe CRS with 100% sensitivity (~78% specificity) in safety rule-out mode and 91.1% sensitivity (93.6% specificity, AUC 0.95 [95% CI 0.91-0.98]) in Youden-optimised mode. Median kinetic lead time was 4 days (range 3-7) before clinical decompensation. Interpretation Biological tolerability is three-dimensional. HARL unifies rate-dependent toxicity across domains spanning minutes to weeks. MTDyn--specifying target level and allowable rate of change--should supplement conventional dose-response assessment.