Bartels-Wilmer, Carli M

Bastiaans, Diane E T

Burger, David M

Colbers, Angela P H

Harbers, Veroniek E M

Heijens, Claudia A W

Smeets, Oscar S N M

Velthoven-Graafland, Kirsten

Vink, Nicole

Warris, Adilia

Archives of Disease in Childhood

English

Aberdeen University Research

A	  new	  paediatric	  formulation	  of	  valaciclovir:	  development	  and	  bioequivalence	  assessment	  	  Diane	  ET	  Bastiaans1,	  Carli	  M.	  Wilmer1,	  Angela	  P.H.	  Colbers1,	  Claudia	  A.W.	  Heijens2,	  Kirsten	  Velthoven-­‐Graafland1,	  Oscar	  S.N.M.	  Smeets3,	  Nicole	  Vink1,	  Veroniek	  E.M.	  Harbers4,	  Adilia	  Warris5,	  David	  M.	  Burger1	  	  1.	  Department	  of	  Pharmacy,	  Radboud	  University	  Medical	  Center,	  Geert	  Grooteplein-­‐Zuid	  10,	  6525	  GA,	  Nijmegen,	  The	  Netherlands.	  2.	  Department	  of	  Pharmacy,	  Zuyderland	  Medical	  Center,	  Henri	  Dunantstraat	  5,	  6419	  PC,	  Heerlen,	  The	  Netherlands,	  3.	  Royal	  Dutch	  Pharmacists	  Association,	  Alexanderstraat	  11,	  2514	  JL,	  The	  Hague,	  The	  Netherlands.	  4.	  Clinical	  Research	  Center	  Nijmegen,	  Radboud	  University	  Medical	  Center,	  Philips	  van	  Leijdenlaan	  15,	  6525	  EX	  Nijmegen,	  The	  Netherlands.	  5.	  Institute	  of	  Medical	  Sciences,	  University	  of	  Aberdeen,	  Foresterhill,	  Aberdeen,	  AB25	  2ZD,	  UK	  	  A	  paediatric	  formulation	  of	  valaciclovir	  with	  acceptable	  palatability,	  good	  pharmaceutical	  quality	  and	  stability	  and	  with	  the	  possibility	  of	  flexible	  dosing	  is	  currently	  not	  available.	  A	  preparation	  of	  valaciclovir	  liquid	  as	  described	  in	  the	  FDA	  label	  information	  was	  found	  not	  to	  be	  adequate	  for	  use	  in	  daily	  practice,	  because	  of	  the	  need	  to	  use	  crushed	  tablets	  and	  the	  short	  shelf	  life.1	  Results	  of	  a	  small	  paediatric	  study	  found	  a	  mean	  relative	  bioavailability	  of	  this	  liquid	  compared	  to	  the	  tablets	  of	  91.1%	  (SD,	  33.1%),	  but	  this	  was	  not	  investigated	  following	  the	  regulatory	  guidance	  for	  bioequivalence	  testing.2	  	  The	  aim	  of	  this	  study	  was	  to	  develop	  a	  new	  paediatric	  formulation	  and	  to	  assess	  the	  bioequivalence	  of	  this	  new	  formulation	  compared	  to	  the	  brand	  named	  valaciclovir	  tablets.	  	  An	  oral	  liquid	  was	  developed	  because	  this	  is	  generally	  considered	  acceptable	  for	  use	  in	  infants	  and	  young	  children.3	  Dosing	  accuracy,	  use	  of	  non-­‐toxic	  excipients,	  palatability	  and	  good	  pharmaceutical	  stability	  for	  an	  acceptable	  period	  of	  time	  were	  all	  taken	  into	  account	  during	  the	  development.	  A	  solution	  was	  developed	  with	  20	  mg/mL	  valaciclovir	  (as	  valaciclovir	  HCl.1	  H2O)	  and	  glycerol	  (42.5%),	  citric	  acid,	  disodium	  hydrogenphosphate	  and	  water	  as	  excipients,	  with	  pH	  3.5	  as	  target.	  The	  new	  formulation	  has	  a	  shelf-­‐life	  of	  at	  least	  six	  months.	  The	  preparation	  method	  and	  developmental	  aspects	  of	  the	  new	  formulation	  has	  been	  included	  in	  the	  Formulary	  of	  the	  Dutch	  Pharmacists	  (FNA)	  and	  is	  freely	  available	  upon	  request.	  	  	  	  Bioequivalence	  of	  the	  new	  formulation	  compared	  to	  the	  innovator	  product	  was	  tested	  in	  a	  randomized,	  single-­‐dose	  (500	  mg),	  open	  label,	  two-­‐period	  crossover,	  phase-­‐I	  trial	  in	  16	  fasting	  healthy	  adult	  volunteers,	  according	  to	  the	  European	  Medicines	  Agency	  (EMA)	  guideline	  for	  investigation	  of	  bioequivalence.4	  Medical	  ethical	  approval	  for	  conduction	  of	  the	  trial	  was	  obtained	  (CMO	  Arnhem-­‐Nijmegen	  Radboud	  University	  Medical	  Center;	  NCT01689285).	  Rate	  and	  extent	  of	  absorption	  was	  determined	  by	  three	  pharmacokinetic	  parameters:	  area	  under	  the	  plasma	  concentration	  time	  curve	  (AUC),	  maximum	  plasma	  concentration	  (Cmax),	  and	  time	  to	  maximum	  plasma	  concentration	  (Tmax).	  These	  were	  calculated	  using	  non-­‐compartmental	  analysis	  (WinNonlin/Phoenix®	  v6.4.	  Pharsight	  Corporation,	  USA).	  	  Subjects	  in	  the	  bioequivalence	  assessment	  had	  a	  median	  age	  of	  31.5	  years	  (range	  19-­‐55),	  body	  mass	  index	  of	  23.7	  (range	  18.8-­‐29.9)	  and	  9	  were	  male.	  Adverse	  events	  possibly	  related	  to	  the	  study	  drug	  were	  reported	  by	  two	  subjects.	  The	  adverse	  page 2 of 3 events	  were	  mild	  and	  both	  subjects	  recovered	  from	  the	  adverse	  events	  within	  24	  hours	  after	  onset	  of	  the	  symptoms.	  The	  geometric	  mean	  pharmacokinetics	  parameters	  are	  shown	  in	  Table	  1	  and	  mean	  plasma	  concentration-­‐time	  profiles	  are	  depicted	  in	  Figure	  1.	  The	  new	  valaciclovir	  solution	  met	  the	  criteria	  for	  bioequivalence	  regarding	  the	  AUC0-­‐12.	  However,	  the	  upper	  limit	  of	  the	  90%CI	  of	  the	  ratio	  for	  Cmax	  was	  just	  above	  the	  125%	  criterion.	  Because	  of	  the	  mild	  toxicity	  profile	  of	  (val)aciclovir,	  it	  is	  not	  expected	  that	  the	  slightly	  higher	  Cmax	  will	  result	  in	  more	  adverse	  events.	  	  	  With	  the	  results	  of	  this	  study	  it	  can	  be	  concluded	  that	  the	  newly	  developed	  valaciclovir	  solution	  can	  be	  used	  as	  an	  alternative	  formulation	  for	  (paediatric)	  patients	  who	  experience	  difficulties	  with	  the	  administration	  of	  valaciclovir	  tablets.	  	  Acknowledgments	  We	  thank	  the	  participants	  of	  the	  bioequivalence	  study.	  From	  the	  department	  of	  pharmacy	  of	  the	  Radboudumc	  we	  thank	  the	  production	  facility	  for	  preparing	  the	  new	  paediatric	  formulation	  and	  the	  analysts	  of	  the	  laboratory	  for	  the	  pharmaceutical	  and	  bio	  analysis.	  	  	  Financial	  disclosure	  This	  study	  has	  been	  performed	  as	  part	  of	  the	  VALID-­‐project	  which	  has	  been	  granted	  by	  The	  Netherlands	  Organisation	  for	  Health	  Research	  and	  Development	  (ZonMW),	  within	  the	  ‘Priority	  Medicines	  for	  Children’	  Programme	  (project	  number:	  113201004).	  	  References	  	  1. Fish DN, Vidaurri VA, Deeter RG. Stability of valacyclovir hydrochloride in extemporaneously prepared oral liquids. Am J Health Syst Pharm 1999;56(19):1957-60. 2. Simon MW, Fish DN, Deeter RG. Pharmacokinetics and safety of valaciclovir in children with Epstein-Barr virus illness. Drugs R D 2002;3(6):365-73. 3. European Medicines Agency. Reflection paper: Formulations of choice for the paediatric population, 2006. 4. European Medicines Agency. Guideline on the investigation of bioequivalence, 2010. 	  	  	  	  Table	  1	  Geometric	  mean	  values	  of	  aciclovir	  pharmacokinetic	  parameters	  Parameter	   Test	  (solution)	  	  (95%CI)	  Reference	  (tablet)	  	  (95%CI)	  Ratio	  T/R	  (%)	  (90%CI)	  Cmax	  (mg/L)	   3.63	  (3.27	  to	  4.02)	   2.98	  (2.59	  to	  3.44)	   121	  (110	  to	  133)	  AUC0-­‐12	  (h*mg/L)	   10.6	  (9.56	  to	  11.7)	   9.96	  (8.71	  to	  11.4)	   106	  (100	  to	  112)	  AUC0-­‐infinity	  (h*mg/L)	   11.0	  (9.95	  to	  12.2)	   10.4	  (9.07	  to	  12.0)	   -­‐	  Residual	  area	  (%)	   3.9	  (2.9	  to	  5.1)	   3.5	  (2.3	  to	  5.3)	   -­‐	  T	  ½	  (h)	   2.75	  (2.50	  to	  3.02)	   2.58	  (2.23	  to	  2.98)	   -­‐	  Tmax	  (h)#	   0.75	  (0.75	  to	  1.44)	   1.25	  (1.00	  to	  1.94)	   -­‐	  #Tmax:	  median	  value	  and	  interquartile	  range	  	  	   	  page 3 of 3 Figure	  1	  Mean	  (+	  SD)	  plasma	  concentration-­‐time	  profile	  of	  the	  new	  valaciclovir	  solution	  and	  the	  reference	  formulation	  (tablet)	  after	  administration	  of	  500	  mg	  valaciclovir.	  	  	  	  	  	  

A new paediatric formulation of valaciclovir : development and bioequivalence assessment

Diane E T Bastiaans

Carli M Bartels-Wilmer

Angela P H Colbers

Claudia A W Heijens

Kirsten Velthoven-Graafland

Oscar S N M Smeets

Nicole Vink

Veroniek E M Harbers

Adilia Warris

David M Burger

Crossref

A new paediatric formulation of valaciclovir: development and bioequivalence assessment

https://aura.abdn.ac.uk/bitstream/2164/8614/1/20160219_VALID_1_letter.pdf

A new paediatric formulation of valaciclovir : development and bioequivalence assessment

Abstract

Similar works

Full text

Available Versions

Aberdeen University Research

Crossref