Bioequivalence and Bioavailability Forum

Ahoy Old Saylor,

❝ ... but as often before I have an unqualified opinion.

Thanx for that!

❝ ... I do not consider it likely that the true concentration rises to 12 after a <LLOQ and then truly drops back to <LLOQ twice and then skyrockets.

But the only truth I have are the data.

❝ I am thus sure in your dataset random variation plays a role.

Sure with probability almost one!
Random variation as always. Otherwise we would not need any statistics.

❝ If I were a regulator I'd probably have accepted if an applicant argued that lag time should be reflecting the time of the last <LLOQ before the median Tmax .

Interesting suggestion.
BTW: You were my favorite regulator if.

❝ ❝ • Do you know of any software which has implemented such?

❝

❝ You are equipped with the power to write clever scripts ?

As you know I have the POWER TO KNOW.
Here is on. Of course in R (cleverness of code may be improved).
But your suggestion yet not considered because of time.
Should be ELM1.
# DEF1: time prior to (of two consecutive) Conc.>LLOQ
# DEF2: time of the first (of two consecutive) Conc.>LLOQ
# DEF3: mean of Def1 and Def2
fTlag <- function(Ctdata1, method="DEF3", consec=2)
{
  #find first of 'consec' consecutive Ct points with Conc>LLOQ  (if available)
  Ctdata1 <- Ctdata1[!is.na(Ctdata1$Conc),]
  n <- length(Ctdata1$time)
 
  if (n<2) return(NA)
 
  Czero <- Ctdata1$Conc[1] # to have it also if multiple dose
                           # but this should be rare
  if (consec<1) consec <- 1
  if (consec>3) consec <- 3
 
  Ctdata1$on <- 0
  on <- 0
  for (i in c(1:n)) {
    if (Ctdata1[i,"Conc"]-Czero > 0){
      on <- on+1
    } else { #Conc=0
      if (on>0) on <- 0
    }
    Ctdata1$on[i] <- on
    if (on==consec) break
  }
 
  ion1 <- which(Ctdata1$on==1)    # indexes with on=1
  if (length(ion1)==0) return(NA) # we have no on -> tlag not est.
 
  ion2 <- which(Ctdata1$on==2)
  if (length(ion2)==0){
    # we have only on=1, may be multiple?
    # take the first? or the last?
    # take time of maximum Conc?
    ion1 <- ion1[1]
    t0 <- Ctdata1$time[ion1-1] # time prior to
    t1 <- Ctdata1$time[ion1]   # time at Conc>LLOQ
  } else {
    ion3 <- which(Ctdata1$on==3)
    if (length(ion3)==0) {
      # we have only 2 consec.
      ion2 <- ion2[1] # take first if multiple?
        t0 <- Ctdata1$time[ion2-2]
        t1 <- Ctdata1$time[ion2-1]
    } else { # 3 consec. values Conc>0
        t0 <- Ctdata1$time[ion2-3]
        t1 <- Ctdata1$time[ion2-2]
    }
  }
  tlag <- NA
  method <- toupper(method)
  if (method=="DEF1") tlag <- t0
  if (method=="DEF2") tlag <- t1
  if (method=="DEF3") {
    if (!is.na(t1)) tlag <- (t1+t0)/2 else tlag <- t0
  }
  return(tlag)
}

BTW2: How thick is the ice nowadays?