Poor bioequivalence with crushed and dissolved tablets
Polly Clayden, HIV i-Base
There are limited paediatric antiretroviral options. Despite manufacture labelling, crushing and/or dissolving tablets, against recommendations, has been reported. Two studies, presented as posters at CROI 2010, looked at bioequivalence of crushed and dissolved Atripla and crushed lopinavir/ritonavir (LPV/r) tablets, compared to whole tablets, in healthy volunteers and HIV-positive children respectively.
Neither strategy met FDA bioequivalence criteria (predefined as, 90%CI 0.8 to 1.25).
Atripla is a fixed dose combination (FDC) tablet combining efavirenz (EFV), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF).
Use of this FDC is limited to patients who can swallow tablets, since there is no liquid formulation currently on the market.
Jennifer King and colleagues from the University of Alabama looked at the bioequivalence of the FDC tablet and a compounded liquid formulation made from the crushed tablet, dissolved in 5 mL of water and diluted with 20 mL of Ora-Sweet oral vehicle.
This was a randomised, single dose, open label, crossover study in 14 healthy volunteers.
Subjects received single doses of both formulations on an empty stomach separated by a 14-day washout period. Samples were taken pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours post dose.
The area under the concentration-time curve (AUC-inf) and maximum concentration (Cmax) of TDF, FTC and EFV were determined using noncompartmental methods. Geometric mean ratio (GMR) of liquid to tablet Cmax, AUC-inf, and 90% confidence intervals (CI) were calculated to determine bioequivalence
The mean ± standard deviation age and weight for the subjects were 33.3 ± 10.9 years and 85.7 ± 18.4 kg, respectively.
The bioequivalence geometric means (percent coefficient of variation) and 90% CI for each drug are shown in Table 1.
Table 1: Bioequivalence, geometric mean ratios for EFV, FTC and TDF liquid and tablet formulations (n=14)
|Drug||Formulation||Cmax (mg/L)||Cmax (mg/L)||AUC-8||AUC-8|
|GM (%CV)||Ratio of GM: Liquid vs tablet (90% CI)||GM (%CV)||Ratio of GM: Liquid vs tablet (90% CI)|
|Tablet||1.5 (39.0)||58.7 (57.5)|
|Tablet||1.8 (32.3)||10.9 (24.7)|
The investigators found only the 90%CI for FTC Cmax and AUC fell within the range to meet bioequivalence in this study.
The 90% CI for EFV Cmax was below the range for bioequivalence and AUC above. TDF Cmax and AUC were approximately 40% and 20% higher with the liquid formulation.
The authors suggested careful consideration before crushing Atripla tablets to construct a compounded oral solution.
A related poster authored by Huy Diep and colleagues from the University of California and Childrens National Medical Center, Washington DC,showed data from a PK study to determine the impact of crushing LPV/r on drug exposure in paediatric patients.
LPV/r is recommended for treating HIV-positive children. Although there is an oral formulation, it tastes unpleasant, contains 42% alcohol, needs to be refrigerated and must be taken with food.
The newer film coated tablet formulation of LPV/r does not require refrigeration and has no food restrictions. Although the manufacturers instructions state that tablets should not be crushed or chewed, routine use of crushed tablets has been reported.
This was a randomised, open-label, cross over study of 12 patients (13 were enrolled but one child refused to take the crushed dose), age 10-16, already taking LPV/r for at least two weeks.
Two separate 12 hour PK sampling following observed doses of LPV/r 400/100mg either whole or crushed tablets were performed. Samples were taken at 0, 1, 2, 4, 6, 8 and 12 hours. Plasma concentrations of LPV and RTV were measured by HPLC and used to calculate non-compartmental area under the curve (AUC) and clearance (CL/F). Median PK values were compared, using the Wilcox signed rank test. Table 1 shows ratios of crushed to whole tablets.
Table 2: Ratios (90% CI) of crushed to whole tablets
|AUC (mg*hr/L)||0.60 (0.48-0.72)||0.003||0.61 (0.45-0.77)||0.005|
|CL/F (L/hr)||1.96 (1.52-2.41)||0.091||2.21 (1.56-2.86)||0.008|
|C12 (mg/L)||0.67 (0.48-0.86)||0.016||0.97 (0.75-1.19)||0.449|
|Cmax (mg/L)||0.81 (0.65-0.98)||0.021||0.86 (0.54-1.19)||0.075|
The investigators reported significantly lower exposure after crushed than whole tablets; approximately 40% decreased oral absorption for LPV and RTV. They noted high interpatient variability, eg crushed/whole LPV AUC ratio range: 5-75%.
The extent and variability of reduced exposure after multiple crushed doses at steady state in HIV-positive children remains unpredictable. The investigators concluded that these data reinforce the need to discourage this dosing practice.
Besides emphasising the importance of following the manufacturers instructions, these data once again highlight the need for appropriate paediatric formulations.
The development of a liquid formulation of efavirenz has been problematic, but the originator company are continuing with the programme and it is hoped that we will have one soon.
For lopinavir/r, as recommended, dividing tablets clearly is not a good option. Cipla are developing sprinkles using melt extrusion technology to make tiny beads. Bioequivalence studies are underway and this formulation will offer a very useful option to the lopinavir/r liquid.
1. King J et al. Assessment of Bioequivalence of Tenofovir, Emtricitabine, and Efavirenz Fixed-dose Combination Tablet Compared with a Compounded Oral Liquid Formulation Derived from the Tablet. 17th CROI, 16-19 February 2010, San Francisco. Poster abstract 605.
2. Diep H et al. Pharmacokinetics of lopinavir/ritonavir crushed vs whole tablets in children. 17th CROI, 16-19 February 2010, San Francisco. Poster abstract 877.