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First Dose Captopril Effects on Blood Pressure and Renal Function

Effect of Captopril first doses on Blood Pressure and Renal Function in Children with Congestive Cardiac Failure Dr Hussain Mulla , Co-Director , Centre for Therapeutic Evaluation of Drugs in Children, University Hospitals of Leicester NHS Trust.

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First Dose Captopril Effects on Blood Pressure and Renal Function

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  1. Effect of Captopril first doses on Blood Pressure and Renal Function in Children with Congestive Cardiac Failure Dr HussainMulla, Co-Director, Centre for Therapeutic Evaluation of Drugs in Children, University Hospitals of Leicester NHS Trust

  2. First Dose Captopril Effects on Blood Pressure and Renal Function Hussain Mulla PhD MRPharmS Senior Research Pharmacist, Paediatric Clinical Pharmacology Centre for Therapeutic Evaluation of Drugs in Children

  3. Background • ACEi doses for children with congestive cardiac failure derive from non-randomised and historical cohort studies (c.f. adults and RCT). • Adverse effects of hypotension (first dose), renal dysfunction, hyperkalaemia, cough • First dose hypotension 11-32% documented in adults • Similar pharmacovigilance data lacking for children • 1 report in children documented first dose hypotension incidence of 15%

  4. Audit Methods • Retrospective (Apr 2007 – Mar 2009) • Data extracted from medical records, drug and TPR charts. • No control of patient or drug related factors that could bias results • Often more than one test dose administered • No a priori calculation of sample size for detection of adverse event rate. • Small sample size (n=48)

  5. Results Mean (range)

  6. Blood Pressure Effects • Test dose of Captopril produced • Mean peak fall in systolic blood pressure post dose of -12.315.6 (p<0.0005) • Mean peak fall in diastolic blood pressure post dose of - 10.8 12.7 (p<0.0005) • 9 patients (18%) developed hypotension (drop in SBP > 25%), 1 of whom had captopril stopped • No significant differences between the ages of patients who developed hypotension

  7. Renal Effects

  8. Conclusion / Discussion • Incidence of first dose hypotension similar to adults • No cases of acute renal failure • Is it safe to initiate captopril in the community by GPs?

  9. Pharmacodynamics Pharmacokinetics Drug Disposition Effect Ka PK/PD Covariates Analysis 2:PK-PD Model of SBP Response to Captopril Initiation

  10. PK PD Response Drug Concentration PK-PD Response Time PK – PD Modelling

  11. Why Model? • Modelling Quantifies the exposure-response relationship • Modelling provides Clarity / Insight • Modelling gives a Mechanistic Understanding of the drug effect • Modelling enables Extrapolation beyond the observed data • Modelling provides scientific rationale to Dose Selection

  12. K-PD Modelling • No Pharmacokinetic data available • Only kinetics of response (BP) is measured • Dose rate as a function of time, drives the PD (rather than traditional PK profile) • A simple 1 compartmental model describes kinetics in the biophase (where drug action takes place)

  13. Biophase Dose (captopril) A(t) Ke Input Rate (IR)=Ke.A(t) Response (Blood Pressure) Kout (Fractional turnover rate) Kin (turnover rate) The Model : Vasodilatory Effects of ACEi Indirect Response (turnover) PD Model

  14. Model Results: Parameter Estimates Kin – zero order synthesis constant for response Kout – first order degradation rate constant for response EDK50 – dose that leads to 50% reduction in SBP ne – not estimated

  15. Model Results: Population Mean Prediction vs Time

  16. Model Results • Peak reduction in BP estimated as 10mmHg • Significant variability around the mean response • Tmax of response estimated as 1.1 hrs • Return to baseline estimated as between 4 – 6 hours

  17. Simulated response with time

  18. Simulated response with time

  19. Simulated response with time

  20. Simulated response with time

  21. Simulated response with time

  22. Conclusion / Discussion • Audit suggests 0.1mg/kg associated with low incidence of asymptomatic hypotension • Variability in response may be related to • Diagnosis / Clinical factors • Baseline BP • Formulation Factors • Fed/Fasted state/Ng tube/GI transit time • Mobile/supine/sitting up • PK/PD modelling can provide further insight into the data • Prospective safety study required to determine true incidence of hypotension

  23. Acknowledgements • Eve Oualid – School of Pharmacy, University of Joseph Fourier, Grenoble, France • Sarah Wheeler – Glenfield Hospital, University Hospitals of Leicester

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