Is saliva a valid substitute for plasma in pharmacokinetic studies of oxycodone and its metabolites in patients with cancer?

Abstract

Purpose Little is known about the pharmacokinetics (PKs) of oxycodone in patients with advanced cancer. There is considerable reluctance to subject these patients to nonessential tests including repeated venipuncture that has been necessary in PK studies to date. We investigated the possibility of using saliva sampling as a simple noninvasive test to investigate opioid PKs. Methods Patients with malignant disease receiving oral sustained release (SR) oxycodone at any dose were asked to provide saliva samples at the same time as blood samples. Samples were not taken within 6 h of a dose of immediate release oxycodone. Plasma and saliva oxycodone and metabolite concentrations were measured using HPLC coupled with tandem mass spectrometric detection. Results One hundred and thirty-nine paired plasma/saliva samples were collected from 43 cancer patients who had been taking SR oxycodone for more than 5 days at doses ranging from 10 to 600 mg/day (median 40 mg/day).Plasma concentrations of oxycodone and noroxycodone ranged from 1.0 to 256.0 and 0.9-269.4 μg/L, respectively. Salivary concentrations of oxycodone (range 0.93-3,620, mean 336 μg/L) were much higher than plasma concentrations (mean 38.2 μg/L). There was a poor correlation between concentrations of both oxycodone and noroxycodone in plasma and saliva over a range of times following dosing (r 2 =0.4641 and 0.3891, respectively). No correlation was shown between salivary pH and oxycodone or noroxycodone concentrations. The majority of patients questioned chose saliva sampling over plasma sampling as the preferred method. Conclusion High levels of both oxycodone and its major metabolite are present in saliva, but this does not provide a valid substitute for plasma when monitoring oxycodone levels for PK studies or therapeutic monitoring.

Development, validation and application of an HPLC–MS/MS method for the determination of fentanyl and nor-fentanyl in human plasma and saliva

“…Similarly mean nor-fentanyl concentration in plasma and saliva was 0.531 and 0.517 µg/L respectively. These data show salivary fentanyl concentrations exceeding plasma concentrations, suggesting the possibility of active transport into saliva is likely, as previously demonstrated for oxycodone [8]. It has been previously described that drugs enter saliva through passive diffusion [25] due to the concentration gradient between plasma and saliva.…”

“…It has been previously described that drugs enter saliva through passive diffusion [25] due to the concentration gradient between plasma and saliva. Furthermore, if the drug exhibits low plasma protein binding, the free (unbound) concentration is available to diffuse from plasma to saliva [8]. However, as fentanyl is almost 85-90 % protein bound [26], there is less free fentanyl available in plasma.…”

“…Furthermore patients with cancer are by definition frail and of poor performance status. There is therefore considerable reluctance on the part of health professionals to subject them to non-essential tests and investigations including repeated venepuncture that has been necessary in pharmacokinetic (PK) studies to date [8].…”

“…The use of saliva as opposed to blood has been shown to be an attractive alternative for therapeutic drug monitoring (TDM) in children because its collection is painless, simpler and cheaper than venesection [9]. In a previous study [8] the majority of patients voiced a preference for saliva sampling over venesection. It has also been used widely for forensic and toxicological investigations [10].…”

Quantitative determination of the enantiomers of methadone in human plasma and saliva by chiral column chromatography coupled with mass spectrometric detection

“…Strong correlations between plasma and saliva concentrations for analgesics such as paracetamol [10] and hydromorphone [13] have been described. Other opioids including codeine [14], diamorphine [11], methadone (for methadone maintenance treatment) [12], morphine [15], dihydrocodeine [16], oxycodone [17], and fentanyl [18], have also been analysed to investigate saliva/plasma (S/P) ratios of drug concentration. Saliva sampling is non-invasive and painless and does not require specially trained personnel.…”