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Abstract
Objective Unlicensed liquid captopril formulations are commonly used to treat children with heart disease. This study assessed the bioequivalence of two liquid preparations against a licensed tablet form.
Design An open label, single dose, three-treatment, three-period, crossover trial.
Setting Outpatient.
Patients Healthy adult volunteers (n=18).
Interventions Each subject was randomly assigned to one of six dosing sequences, and dosed with 25 mg captopril on each of three dosing visits separated by a washout of at least 14 days. Blood samples for pharmacokinetic analysis were taken at regular intervals (0 min to 10 h) post-dose.
Main outcome measures Bioequivalence of the formulations would be concluded if the 90% CI for the estimated ratio of the means of Cmax (maximum plasma concentrations) and area under curve(AUC) (extent of absorption) lay entirely within the range 0.8 to 1.25
Results Both liquid formulations failed the bioequivalence assessment with respect to Cmax and AUC. The 90% CI of the mean ratios of liquid/licensed tablet for both Cmax and AUC, fell outside the 0.8 to 1.25 limits. There was also considerable within-subject variability in Cmax (97.5%) and AUC (78.5%).
Conclusions Unlicensed captopril formulations are not bioequivalent to the licensed tablet form, or to each other, and so cannot be assumed to behave similarly in therapeutic use. Thus formulation substitution must be done with care and may require a period of increased monitoring of the patient. There is also significant within-subject variability in performance which has clinical implications with respect to titrating to an optimum therapeutic dose.
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Background
Captopril was the first angiotensin converting enzyme inhibitor to be introduced into clinical practice. Although its use in children was initially based on randomised controlled trials in adult patients with cardiovascular diseases, over time a combination of clinical experience, case series reports and observational studies have provided clinicians with practical evidence of its efficacy in managing children with heart conditions.1 However, to date no marketed captopril product in the UK has a license for use in children. Moreover, only the tablet formulation is licensed for adults, that is, there are no licensed oral liquid preparations for any age group. Hence, presently in the UK, children receiving captopril (off label) who are unable or unwilling to take the tablet preparation are given an unlicensed liquid preparation or a crushed or split tablet dissolved in water.
What is already known on this topic
▶ Presently, there is no licensed liquid formulation of captopril available in the UK for the treatment of children with heart disease.
▶ As a consequence, unlicensed liquid captopril formulations from a variety of ‘specials’ manufacturers or imported from outside the EU are used interchangeably.
What this study adds
▶ Unlicensed liquid captopril formulations have been shown not to be bioequivalent to a licensed tablet form.
▶ The practice of prescribing bio-inequivalent formulations interchangeably may contribute to unpredictable drug response and suboptimal therapy.
▶ Clinical staff in tertiary care should ideally ensure that children are maintained on the same formulation from the same source for the duration of treatment.
The formulation of a medicine influences the rate and the extent to which the active drug in the medicine is absorbed into the systemic circulation (bioavailability). Consequently, a drugs' formulation is a vital determinant of its efficacy and toxicity.2 Since there is no bioavailability data regarding any unlicensed liquid captopril formulation currently in use in the UK, it is unclear whether captopril-related efficacy and toxicity are due to the drug per se or due to bioavailability issues related to the formulation.3 4
We recently found that there are several different unlicensed liquid captopril preparations used in the UK and these preparations are either procured from a number of ‘specials’ manufacturers or imported from outside the EU. Moreover, we noted that these formulations are dispensed interchangeably without reference to the possibility that each has a different absorption profile.5 The clinical implications of this problem for children with heart disease are difficult to quantify as the problems faced by such children are often complex. However, it seems possible that children using liquid captopril formulations may be underdosed and therefore have poor symptom control and/or over-dosed causing unwanted and unnecessary side effects.
At present, there is no evidence to establish whether liquid captopril preparations deliver doses consistently and predictably and whether these formulations are bioequivalent to the captopril tablet. In this study, we aimed to compare the bioequivalence of two unlicensed liquid captopril preparations against a licensed tablet form in a group of healthy adult volunteers. The use of healthy adult volunteers to determine bioequivalence between formulations (including those intended for children) is the recognised approach by pharmaceutical regulatory authorities and is clinically and scientifically credible.6
Methods
The study received approval from the Leicestershire, Northamptonshire and Rutland Research Ethics Committee 2 (08/H0402/47) and also clinical trial authorisation from the Medicines Healthcare Regulatory Agency, UK.
Study design
An open label, single dose, three-treatment, three-period, six-sequence crossover trial.
Formulations
Two unlicensed oral liquid (test) formulations of captopril underwent evaluation. Formulation A is a captopril solution branded ‘Capoten’ (Captopril 25 mg/5 ml) made by Bristol Myers Squibb, Australia. Formulation B is a captopril suspension (Captopril 25 mg/5 ml Oral Suspension) made by Nova Laboratories, Leicester, UK, a ‘specials’ manufacturer. Formulation C is a licensed tablet formulation (Captopril 25 mg tablet; APS, Edinburgh, UK) and was used as the reference. The two liquid formulations have been studied in vitro with respect to their organoleptic characteristics, pH, osmolarity, viscosity, dose uniformity and physicochemical and microbial stability during simulated ‘in use’ conditions (each preparation was sampled twice daily with an oral syringe rinsed under tap water in between measurements to mimic the use in practice of the liquids for 8 weeks) and under their recommended storage conditions for 6 months. The composition of the two liquids were different but both pH were acidic (3 and 4 for Formulation A and B respectively) and optimal for the stability of captopril. The main differences were in colour, opacity, taste, smell, viscosity and osmolarity. Formulation B suspension is 5000 times more viscous than Formulation A solution and hyper-osmolar (618 mOsm/l) compared to Formulation A (hypo-osmolar, 182 mOsm/l). Formulation A solution is transparent, unsweetened, unflavoured and has a strong sulphur taste and smell (rotten egg), whereas in Formulation B suspension a ‘forest fruit’ flavouring agent masks the poor smell and the taste was sweet. It is to be noted that the suspension is prepared by suspending crushed captopril tablets in a sweetening and suspending vehicle. However the highly soluble captopril is actually dissolved like in Formulation A. The study showed that both preparations, even if different, meet pharmaceutically comparable and clinically acceptable standards for being in use for 8 weeks and over a shelf life of 6 months.
Patients
The study involved 18 healthy adult volunteers aged 18–55 with a body mass index between 19 and 29. All study volunteers underwent clinical and biochemical screening procedures prior to dosing. Smokers and those with renal or hepatic impairment, cardiac disease and gastrointestinal inflammatory disease were excluded from the study.
Dosing with captopril
Subjects were randomly assigned to one of six dosing sequences based on a serially balanced ‘Williams Latin square’ design. Each dosing visit was separated by a washout of at least 14 days (figure 1). After an overnight fast, each volunteer was given a single 25 mg oral dose of captopril (formulation A, B or C) with 0.25 litre of water. After dosing, each volunteer was closely monitored for blood pressure (BP), heart rate and adverse reactions and were not allowed water (2 h), bed rest (3 h), food (2 h) and vigorous exercise (12 h).
Disposition of volunteers.
Blood sampling
Each volunteer had blood samples taken immediately before study drug administration (time 0) and at regular intervals (30 min to 10 h) post-dose. All blood samples were collected (EDTA tubes) and separated by centrifugation. The plasma from each sample was stored at −20°C until analysis.
Plasma captopril measurement
Concentrations of captopril in plasma were measured by liquid chromatography-mass spectrometry using a validated method.7 The validation range for captopril using this method was determined to be 25–1500 ng/ml.
Pharmacokinetic and statistical analysis
Standard pharmokinetic (PK) parameters (time to maximum (Tmax) plasma concentration, maximum plasma concentrations (Cmax), area under the concentration versus time curve from time 0 to the last quantifiable time point (AUC0−t), area under the concentration versus time curve from time 0 extrapolated to time infinity (AUC0−∞) and terminal half life) were calculated using standard methods. The calculations were conducted using WinNonLin V.4.4. All plasma concentrations reported as missing or below the lower limit of quantification were excluded from the analysis. Tmax and Cmax were taken from the observed concentration-time profile. For calculating the terminal half life a minimum of three of the last data points were used and the r2 was greater than 0.90.
Descriptive statistics for the PK parameters were obtained for the test and reference formulations prior to analysis (table 1). Bioequivalence of the test and reference formulations was assessed on the basis of Cmax, AUC0−t and AUC0−∞. These PK parameters were logarithmically transformed and analysed using a fixed-effects general linear model with factors accounting for sequence, subjects nested in sequence, period and treatment. For each contrast the ratio of estimated least squares means was obtained from the model and a 90% CI calculated. Estimates for the ratio of the means of the logarithmically transformed parameters, and the limits of the 90% CI, were then obtained by exponentiation.
Summary statistics for Cmax, AUC0−t and AUC0−∞
Bioequivalence for two formulations would be concluded if the 90% CI for the estimated ratio of the means of the logarithmically transformed observed values lay entirely within the range 0.8–1.25.6 Statistical analyses were performed using SAS V.9.1.3.
Results
Demographic details of volunteers (n=18) are shown in table 3. In relation to formulation B, one volunteer (visit 1) was not able to be dosed and therefore data analysis for this formulation is limited to 17 subjects. As data analysis was performed on an ‘intention to treat’ basis, data for the subject relating to formulations A and C was included in the analysis.
Volunteer demographics
PK analysis
Summary statistics for the PK parameters determined for all three formulations are shown in tables 1 and 2.
Summary statistics for Tmax and t½
Assessment of bioequivalence
Results of the pair-wise comparisons of formulations A, B and C for captopril are shown in table 4. There was no difference between the three formulations in the Tmax plasma concentration, with a median Tmax of 1 h. However, both test formulations, A and B, failed the bioequivalence assessment with respect to Cmax and AUC (extent of absorption). Although formulation B (suspension) performed slightly better than formulation A (solution), in both cases bioavailability was reduced compared to the tablet.
Bioequivalence assessment: point estimate and 90% CI for ratio of the means for the logarithmically transformed Cmax, AUC0−t and AUC0−∞
The mean AUC0−∞ and mean Cmax of the two liquid formulations A and B were compared to the licensed formulation, C, ratiometrically. For AUC, the A/C and B/C point estimate ratios (90% CI) were 82% (55% to 122%) and 94% (63% to 142%), respectively. For Cmax the A/C and B/C point estimate ratios (90% CI) were 73% (46% to 117%) and 80% (50% to 129%), respectively. The 90% CIs for both unlicensed liquid formulations (A & B) fell outside accepted criteria (80% to 125%) for bioequivalence (7). In addition, a comparison of A versus B revealed that they were not bioequivalent to each other. For this latter comparison, although the mean ratios for Cmax, AUC0−t and AUC0−∞ were within accepted limits, the 90% CI fell partly outside accepted limits (table 4). The study also revealed significant overall within-subject variability (percentage coefficient of variation) in Cmax (97.5%), AUC0−t (77.6%) and AUC0−∞ (78.5%).
Safety evaluation
Data for all 18 volunteers entered for the study were included in the safety evaluation. Two moderate (unrelated to drug) and three mild adverse events were recorded in five volunteers. The overall evaluation of laboratory results showed no significant changes or trends between screening and final examination. The vital signs of all the volunteers recorded throughout the study were satisfactory. No clinically significant abnormal physical findings were made at pre-study or post-study screening. Test and reference formulations were well tolerated in these healthy volunteers at the dose given.
Discussion and conclusions
This study provides evidence that two unlicensed liquid captopril formulations commonly used in paediatric practice are not bioequivalent to the licensed tablet formulation with respect to Cmax and AUC within the narrow limits as defined by the European Medicines Agency.6 In addition, the liquid forms were not shown to be bioequivalent to each other.
Alterations in the bioavailability of any drug with different formulations have the potential to affect the therapeutic response and/or increase adverse events, such as hypotension in relation to captopril. For some drugs altered efficacy and safety can be mitigated by close monitoring of therapeutic and safety end points for example using white cell count to monitor mercaptopurine dosing in children with leukaemia and by restricting patients to a single formulation. However, for captopril any mitigation through close monitoring of blood pressure, cardiac and renal function while establishing an appropriate dosing regimen are likely to be lost if bio-inequivalent formulations are dispensed interchangeably. This practice will inevitably contribute to unpredictable drug response and suboptimal therapy.5 Thus, healthcare professionals must exercise caution when substituting captopril formulations and patients may require a period of increased monitoring.
We also noted high within-subject variability in systemic exposure (Cmax and AUC) of captopril. The implications for patient management of this variability are unclear but these findings suggest that in children and adults between doses there may be significant fluctuations in captopril plasma levels and hence therapeutic effect. The source of the high within-subject variability in plasma captopril concentration needs further investigation. It may be a ‘formulation effect’, such as ‘dissolution rate’, which can limit drug absorption. However, as captopril is a highly soluble drug this explanation seems unlikely.8 Other explanations include variable permeability perhaps due to transporter uptake and efflux that could influence absorption across enterocytes into the systemic circulation.8 9 It is perhaps also important to note that in general unlicensed formulations are not subject to the same quality control as licensed products and therefore batch to batch variations in drug content may contribute to within-subject variability.
These findings highlight wider issues relating to drug dosing in children. Although the use of unlicensed medicines is often borne out of necessity (eg, absence of a suitable licensed formulation), clinicians, pharmacists and parents should not assume that dose delivery will be equivalent to the licensed form or to another, unlicensed, formulation of a drug. Indeed the results of this study suggest that healthcare professionals should increase pharmacovigilance in patients prescribed these therapies. Moreover, once patients requiring chronic therapy have been established on an unlicensed formulation, whenever possible, they should be maintained on the same formulation from the same source for the duration of treatment. Clearly, there is a need for further studies that evaluate the biopharmaceutical properties of unlicensed formulations, particularly those that have narrow therapeutic ranges and/or are prescribed for critical illnesses. Performance standards for such unlicensed products (that already exists in the British Pharmacopoeia for a limited number of extemporaneous preparations) would be a huge step forward. However, in addition, there needs to be greater awareness among healthcare professionals on the data available to support the quality, safety and efficacy of the unlicensed product. Where the availability of such data is limited, a risk-assessment should be conducted prior to procurement of the product. The risk-benefit profile for the product (quality, safety and efficacy) needs to be considered in the context of the disease and the best needs of the child and should involve both the paediatrician and the pharmacist.
In conclusion, unlicensed captopril formulations have not been shown to be bioequivalent to a licensed tablet form, or to each other, and so cannot be assumed to behave similarly in therapeutic use. There is significant within-subject variability that has significant clinical implications with respect to titrating to an optimum therapeutic dose. This study also demonstrates that healthcare professionals must not assume that unlicensed formulations designed for use in children are bioequivalent to a licensed formulation. Thus formulation substitution must be done with care and may require a period of increased monitoring of the patient.
Footnotes
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Funding This study was funded by the National Institute for Health Research—Research for Patient Benefit Programme (PB-PG-0107–12267).
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Competing interests None.
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Ethics approval This study was conducted with the approval of the Leicestershire, Northamptonshire & Rutland REC 2.
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Provenance and peer review Not commissioned; externally peer reviewed.