{"id":10492,"date":"2010-06-01T15:35:35","date_gmt":"2010-06-01T15:35:35","guid":{"rendered":"http:\/\/i-base.info\/htb\/?p=10492"},"modified":"2010-06-01T15:35:35","modified_gmt":"2010-06-01T15:35:35","slug":"poor-bioequivalence-with-crushed-and-dissolved-tablets","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/10492","title":{"rendered":"Poor bioequivalence with crushed and dissolved tablets"},"content":{"rendered":"

Polly Clayden, HIV i-Base<\/strong><\/p>\n

There are limited paediatric antiretroviral options. Despite manufacture labelling, crushing and\/or\u00a0 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.<\/p>\n

Neither strategy met FDA bioequivalence criteria (predefined as, 90%CI 0.8 to 1.25).<\/p>\n

Atripla is a fixed dose combination (FDC) tablet combining efavirenz (EFV), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF).<\/p>\n

Use of this FDC <\/sup>is limited to patients who can swallow tablets, since there is no liquid formulation currently on the market.<\/p>\n

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.<\/p>\n

This was a randomised, single dose, open label, crossover study in 14 healthy volunteers.<\/p>\n

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.<\/p>\n

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<\/p>\n

The mean \u00b1 standard deviation age and weight for the subjects were 33.3 \u00b1 10.9 years and 85.7 \u00b1 18.4 kg, respectively.<\/p>\n

The bioequivalence geometric means (percent coefficient of variation) and 90% CI for each drug are shown in Table 1.<\/p>\n

Table 1: Bioequivalence, geometric mean ratios for EFV, FTC and TDF liquid and tablet formulations (n=14)<\/strong> <\/p>\n\n\n\n\n\n\n\n\n\n\n
Drug<\/td>\nFormulation<\/td>\nCmax (mg\/L)<\/td>\nCmax (mg\/L)<\/td>\nAUC-8<\/td>\nAUC-8<\/td>\n<\/tr>\n
GM (%CV)<\/td>\nRatio of GM: Liquid vs tablet\u00a0 (90% CI)<\/td>\nGM (%CV)<\/td>\nRatio of GM: Liquid vs tablet\u00a0 (90% CI)<\/td>\n<\/tr>\n
EFV<\/strong><\/td>\nLiquid<\/td>\n1.3 (28.8)<\/td>\n0.86\n

(0.75-1.04)<\/p><\/td>\n

56.7 (80.0)<\/td>\n0.97\n

(0.62-1.26)<\/p><\/td>\n<\/tr>\n

Tablet<\/td>\n1.5 (39.0)<\/td>\n58.7 (57.5)<\/td>\n<\/tr>\n
FTC<\/strong><\/td>\nLiquid<\/td>\n2.1 (21.0)<\/td>\n1.15\n

(0.97-1.25)<\/p><\/td>\n

10.8 (15.9)<\/td>\n0.99\n

(0.91-1.05)<\/p><\/td>\n<\/tr>\n

Tablet<\/td>\n1.8 (32.3)<\/td>\n10.9 (24.7)<\/td>\n<\/tr>\n
TDF<\/strong><\/td>\nLiquid<\/td>\n0.3 (27.7)<\/td>\n1.38\n

(1.12-1.70)<\/p><\/td>\n

2.2 (36.3)<\/td>\n1.21\n

(1.07-1.40)<\/p><\/td>\n<\/tr>\n

Tablet<\/td>\n0.2(47.8)<\/td>\n1.8 (29.2)<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

The investigators found only the 90%CI for FTC Cmax and AUC fell within the range to meet bioequivalence in this study.<\/p>\n

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.<\/p>\n

The authors suggested careful consideration before crushing Atripla tablets to construct a compounded oral solution.<\/p>\n

A related poster authored by Huy Diep and colleagues from the University of California and Children\u0092s 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.<\/p>\n

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.<\/p>\n

The newer film coated tablet formulation of LPV\/r does not require refrigeration and has no food restrictions. Although the manufacturer\u0092s instructions state that tablets should not be crushed or chewed, routine use of crushed tablets has been reported.<\/p>\n

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.<\/p>\n

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.<\/p>\n

Table 2: Ratios (90% CI) of crushed to whole tablets <\/strong> <\/p>\n\n\n\n\n\n\n\n
<\/strong><\/td>\nLPV<\/td>\np-value<\/td>\nRTV<\/td>\np-value<\/td>\n<\/tr>\n
AUC (mg*hr\/L)<\/td>\n0.60 (0.48-0.72)<\/td>\n0.003<\/td>\n0.61 (0.45-0.77)<\/td>\n0.005<\/td>\n<\/tr>\n
CL\/F (L\/hr)<\/td>\n1.96 (1.52-2.41)<\/td>\n0.091<\/td>\n2.21 (1.56-2.86)<\/td>\n0.008<\/td>\n<\/tr>\n
C12 (mg\/L)<\/td>\n0.67 (0.48-0.86)<\/td>\n0.016<\/td>\n0.97 (0.75-1.19)<\/td>\n0.449<\/td>\n<\/tr>\n
Cmax (mg\/L)<\/td>\n0.81 (0.65-0.98)<\/td>\n0.021<\/td>\n0.86 (0.54-1.19)<\/td>\n0.075<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

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%.<\/p>\n

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. <\/p>\n

comment <\/strong><\/h2>\n

Besides emphasising the importance of following the manufacturer\u0092s instructions, these data once again highlight the need for appropriate paediatric formulations.<\/strong><\/p>\n

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.<\/strong><\/p>\n

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.<\/strong><\/p>\n

References<\/p>\n

1.\tKing 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.\u00a0 Poster abstract 605.<\/p>\n

http:\/\/www.retroconference.org\/2010\/Abstracts\/37400.htm<\/a><\/p>\n

2. \u00a0 Diep H et al. Pharmacokinetics of lopinavir\/ritonavir crushed vs whole tablets in children. 17th CROI, 16-19 February 2010, San Francisco.\u00a0 Poster abstract 877.<\/p>\n

http:\/\/www.retroconference.org\/2010\/Abstracts\/37445.htm<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

Polly Clayden, HIV i-Base There are limited paediatric antiretroviral options. Despite manufacture labelling, crushing and\/or\u00a0 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 …<\/p>\n","protected":false},"author":4,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,32,34],"tags":[64],"class_list":["post-10492","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-paediatric-care","category-pk-and-drug-interactions","tag-croi-2010"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/10492","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/users\/4"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=10492"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/10492\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=10492"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=10492"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=10492"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}