Ondansetron Clinical Pharmacokinetics Fausto Roilal and Albano Del Favero2
1 Medical Oncology Division, Polic1inico Hospital, Perugia, Italy 2 Department of Internal Medicine and Oncological Sciences, University of Perugia, Perugia, Italy
Summary Ondansetron is a potent and highly selective serotonin S-HT3-receptor antagonist which has demonstrated important antiemetic activity and good tolerability in the prevention of chemotherapy-induced nausea and vomiting.
Ondansetron is completely and rapidly absorbed from the gastrointestinal tract after oral administration, and does not accumulate with repeated oral administration. Owing to hepatic first-pass metabolism, its bioavailability is only about 60% compared with ondansetron administered by infusion over IS minutes. Bioavailability is slightly increased when administered after a standard meal, and is not influenced by coadministration of antacids; a slightly enhanced bioavailability has been observed in patients with cancer. Since the time to reach peak concentration is O.S to 2 hours after oral ingestion, the drug should be administered at least 30 minutes before chemotherapy. Possible alternative ways of administration of ondansetron include intramuscular, subcutaneous and rectal administration, and oral controlled-release formulations.
Ondansetron is widely distributed (volume of distribution approximately 160L) and binds moderately (70 to 76%) to plasma proteins; the elimination half-life averages approximately 3.8 ± 1 hours. Clearance occurs by hepatic me-
96 Roila & Del Favero
tabolism (95%) rather than renal excretion. Metabolites do not playa role in the activity of the drug, and there is no evidence of genetic polymorphic metabolism.
Although aging is associated with decreased clearance and increased bioavailability, dosage adjustments are not required for the elderly, and may be necessary only in patients with severe hepatic impairment. Chemotherapeutic agents do not seem to modify the pharmacokinetics of ondansetron.
There remains the question of whether control of emesis is related to systemic availability of ondansetron and, in consequence, the optimal dose and schedule of ondansetron is still to be identified with certainty.
Ondansetron is a potent and highly selective serotonin 5-HT3-receptor antagonist which has demonstrated important antiemetic activity and good tolerability in the prevention of chemotherapy-induced nausea and vomiting.[11 This review of the pharmacokinetics of ondansetron aims to identify clinically relevant information which may contribute to better utilisation of the drug.
The ondansetron pharmacokinetic data reviewed here are from a relatively small number of studies, conducted mainly in healthy volunteers and characterised by a variety of dosages and schedules of administration, which are sometimes different from those currently recommended for ondansetron. However, despite these limitations, the available data can provide clinicians with useful guidelines for rational use of the drug.
1. Physicochemical Properties
Ondansetron hydrochloride dihydrate (ondansetron) is a synthetic compound, with the structure shown in figure 1. It is a fairly lipophilic compound (the diffusion coefficient log D = 2.2 at pH 10.6), exists as a racemate and possesses one asymmetric centre. Ondansetron is a weak base (pKa = 7.4), and its solubility in aqueous solution is markedly reduced at pH values> 5.7.[21
2. Analytical Procedures
Analysis of the ondansetron base concentrations in plasma has been performed using high performance liquid chromatography (HPLC) and high performance thin-layer chromatography (HPTLC). [31 The HPLC procedure (which generally involves
Fig. 1. Chemical structure of ondansetron .• indicates an asymmetric centre.
solid-phase extraction and ultraviolet detection) is accurate and precise, with a detection range for ondansetron of 1.0 to 20 ~glL in plasma. Recently, the development of a radioimmunoassay technique (incorporating solid-phase extraction) which is suitable for the determination of the sub-nanogram base concentrations of ondansetron in plasma has been described.l41 An HPLC method for the assay of R( - )-ondansetron and S( + )-ondansetron has also been developed and validated.[51
3. Pharmacokinetic Profile
The pharmacokinetic characteristics of ondansetron have been studied in healthy individuals and patients undergoing anticancer chemotherapy, of various ages and both sexes. Of particular interest are those studies in which single or repeated 8mg oral doses and single 8mg or 0.15 mg/kg rapid (15-minute) infusions have been employed. This is because these types of dosage and administration schedule are similar to those most frequently used clinically. Tables I and II summarise the results from the most important pharmacokinetic studies
Clin. Pharmacokinet. 29 (2) 1995
@ Table I. Summary of pharmacokinetic data of ondansetron determined in healthy individuals 0 » ::s n Study No. of patients Dose Route F Cmax tmax t%~ AUCa-_ V", CL CLR P-iii· Pl '5 (age, years) (%) (~glL) (h) (h) (~g/L· h) (Ukg) (mlimin)a (ml/min)a ::s it [J>
To convert to Uh, multiply by 0.06. 0. a 3 b Llh/kg. 0. 0 c Geometric means and 95% confidence intervals were used, except for tmax (median and range) and t'/,~ [arithmetic mean (Blackwell) or harmonic mean with 95% confidence intervals 0
'" (Colthup study)]. s· ~ d 14 patients. I\) e 9 patients.
'" Abbreviations: AUCa-_= area under the concentration-time curve from time zero to infinity; Cmax= peak plasma drug concentration after single-dose administration; CI = continuous infusion; 3 CL = total body clearance of drug from plasma; CLR = renal clearance of drug from plasma; F = bioavailability; IV = intravenous; t'I,~ = elimination half-life; tm., = time to Cmax; PO = oral :g administration; tid = three times daily; V" = apparent volume of distribution at steady-state. '-0 en '-.l
carried out wi th healthy indi viduals and cancer patients, respectively.
3.1 Absorption
In healthy individuals, ondansetron is completely and rapidly absorbed after oral administration. The drug is first detected in plasma 30 minutes after administration of a single 8mg oral dose; time to reach peak concentration (trnax) is 1.0 to 2.1 hoursp,7,8] Despite the similar demographic characteristics (age and sex) of the study groups, the maximum plasma concentrations (Crnax) show considerable interindividual variability, ranging between approximately 20 and 40 !J,g/L. Crnax and trnax values obtained after intravenous administration also vary, according to the dose, duration of infusion, and blood sampling time (see tables I and II). When compared with an 8mg intravenous infusion over 15 minutes, oral ondansetron has approximately 50 to 70% bioavailability because of firstpass metabolism.[13]
In patients with cancer, absorption of ondansetron has been less extensively studied. The only study with results that are comparable to those achieved in healthy individuals shows that, following an 8mg oral dose, the Crnax and trnax values are in the same range as those for healthy individuals of similar ages.[II] This study also shows that bioavailability is enhanced in patients with cancer, averaging 85 to 87% with considerable variability among the patients (range 60 to 165%).[11] However, it is likely that these changes are related to variation in the metabolism of ondansetron rather than to changes in absorption (see section 3.3).
Area under the plasma concentration-time curve (AUC) and Crnax values determined in patients with cancer after administration of oral ondansetron 8mg were generally found to be higher than those of younger, healthy individuals; trnax values were usually in the same range for both groups.[3,9,14]
Two dose-ranging studies (with 12[8] and 25[15] healthy participants, respectively) have evaluated the influence of increasing oral doses on the absorption of ondansetron. Both studies found a nonproportional increase in systemic availability with
Clin. Pharmacokinet. 29 (2) 1995
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carried out wi th healthy indi viduals and cancer patients' respectively.
3.1 Absorption
In healthy individuals, ondansetron is completely and rapidly absorbed after oral administration. The drug is first detected in plasma 30 minutes after administration of a single 8mg oral dose; time to reach peak concentration (tmax) is 1.0 to 2.1 hours.l3,7,8] Despite the similar demographic characteristics (age and sex) of the study groups, the maximum plasma concentrations (emax) show considerable interindividual variability, ranging between approximately 20 and 40 IJ,g/L. emax and tmax
values obtained after intravenous administration also vary, according to the dose, duration of infusion, and blood sampling time (see tables I and II). When compared with an 8mg intravenous infusion over 15 minutes, oral ondansetron has approximately 50 to 70% bioavailability because of firstpass metabolism.[13]
In patients with cancer, absorption of ondansetron has been less extensively studied. The only study with results that are comparable to those achieved in healthy individuals shows that, following an 8mg oral dose, the emax and tmax values are in the same range as those for healthy individuals of similar ages.[II] This study also shows that bioavailability is enhanced in patients with cancer, averaging 85 to 87% with considerable variability among the patients (range 60 to 165%).[11] However, it is likely that these changes are related to variation in the metabolism of ondansetron rather than to changes in absorption (see section 3.3).
Area under the plasma concentration-time curve (AUC) and emax values determined in patients with cancer after administration of oral ondansetron 8mg were generally found to be higher than those of younger, healthy individuals; tmax values were usually in the same range for both groupsp,9,14]
Two dose-ranging studies (with 12[8] and 25[15] healthy participants, respectively) have evaluated the influence of increasing oral doses on the absorption of ondansetron. Both studies found a nonproportional increase in systemic availability with
Clin. Pharmacokinet. 29 (2) 1995
Ondansetron Clinical Pharmacokinetics 99
Table III. Dose-ranging studies of ondansetron administered as a single oral dose in healthy individuals
Dose Cm"x (llg/L) AUC (llglL· h) (mg) from Bryson % from Haberer % from Bryson % from Haberer %
et al.181 increase" et al.1151 increase" et al.181 increase" et a1.115) increase"
8 19.9 100 24.7 100 101.5 100 145.1 100
16 59.8 150 58.4 118 337.8 166 366.4 126
32 136.3 171 143.5 145 590.9 146 858.3 148
48 254.3 213 1323.6 217
64 348.5 219 327.4 166 1941.9 239 2107.2 182
a Percentage of the value predicted from the 8mg dose.
Abbreviations: AUC = area under the plasma concentration-time curve; Cmax = peak plasma drug concentration after single-dose administration.
8, 16,32,48 and 64mg of ondansetron (table III). This suggests a saturation of the first-pass metabolism.
The effects of different formulations on absorption have also been studied. One result is that absorption of ondansetron is not rate-limited by dissolution. In a study with 24 healthy male volunteers, the bioavailability of an 8mg oral tablet formulation of ondansetron (already on the market) was in fact shown to be equivalent to that of an oral solution, suggesting that tablets achieve complete and rapid dissolution in VivO.[16]
The feasibility of either controlled-release or suppository formulations of ondansetron has been evaluated by determining the absorption of a solution (8mg) administered into the colon (via a nasogastric tube or rectally using a retention enema).l17] Cmax and tmax values were similar to those obtained after the standard oral administration of ondansetron 8mg. In addition, absolute bioavailability after oral administration (71 ± 14%), colonic infusion (74 ± 26%) and rectal administration (58 ± 18%) was not significantly different.
It appears from the above that ondansetron is readily and rapidly absorbed after all types of enteral administration. This result is unsurprising, as absorption of ondansetron was found to be complete in an in vitro model for studying drug absorption (using a well differentiated human intestinal cell line), occurring by passive diffusion via a transcellular pathway across intestinal mucosa, probably due to the lipophilic characteristics of ondansetron.[18]
Absorption of an intramuscular formulation of ondansetron was studied in a double-blind, doubledummy, placebo-controlled, randomised crossover study with 16 healthy male participants.l 19] The dose used was ondansetron 4mg, administered intravenously or intramuscularly. Intramuscular ondansetron was rapidly absorbed, and Cmax was found to be 39% compared with the value for intravenous administration. The systemic availability obtained with the two different routes of administration was similar. The bioavailability of ondansetron administered subcutaneously has not been reported, but case studies suggest that the drug is effective when administered in this way.l20,21]
Gastric pH and the presence of food influence the absorption of many drugs; possible interaction of ondansetron with antacids and food has been studied. Ondansetron is a weak base, and under the acidic conditions of the stomach exists in an ionised, water-soluble form. Solubility is markedly reduced at pH > 6; thus, theoretically, fasting conditions or administration of antacid drugs might affect dissolution of ondansetron tablets and hence its bioavailability.
A randomised, crossover study evaluated the bioavailability of an 8mg tablet of ondansetron under various conditions. The 12 healthy male participants were variously fasting or fed, had fasted, or had taken an antacid (magnesium hydroxide plus aluminium hydroxide).[16] The results did not show a statistically significant influence of antacid on the extent of ondansetron absorption (as evi-
Clln. Pharmacokinet. 29 (2) 1995
100
denced by no change in AVe values), or on the rate of absorption (as evidenced by tmax values), compared with those who were fasting. However, the presence of food slightly (yet statistically significantly) enhanced the extent of ondansetron absorption, without affecting tmax • Despite these differences, the results of the study gave no indication that the presence or absence of food or antacids alters the absorption of ondansetron to a clinically significant extent.
In summary, we can conclude that: • ondansetron in tablet form is rapidly dissolved
and absorbed, and absolute bioavailability is approximately 60%;
• oral ondansetron formulations intended to prevent emesis should be given to patients at least 30 minutes prior to chemotherapy;
• nonlinear absorption occurs with increasing oral doses of ondansetron;
• the presence of food and antacids does not modify the absorption of ondansetron in a clinically significant way;
• absorption after intramuscular, colonic or rectal administration is satisfactory and, therefore, new formulations of ondansetron may become a useful adjunct to the presently available oral and intravenous formulations , in selected patients.
3.2 Distribution and Protein Binding
Typical, independent pharmacokinetic data are summarised in table I (studies in healthy people) and table II (studies in cancer patients). Mean concentration-time curves of ondansetron 8mg after oral or intravenous rapid infusion (using the proposed clinical regimens) are illustrated in figure 2. With either route of administration, ondansetron concentration increases rapidly in the plasma, reaching maximal concentration at the end of infusion or 1 to 1.5 hours (on average) after oral administration, respectively. The concentration then decreases in a first-order fashion. The elimination half-life (tY2~) averaged approximately 3.8 ± 1.0 hoursP2)
Ondansetron has a relatively large volume of distribution (Vd) in adults, approximately 160U9)
Fig. 2. Ondansetron bioavailability study: mean plasma concentrations (for 18 study participants; from Colthup and Palmer,[3] with permission).
The mean Vd is 1.9 L/kg; since total body water corresponds to 0.9 L/kg, this means that ondansetron is taken up by tissue membranes.(22) The bloodplasma ratio of 0.83 for ondansetron indicates that the drug distributes into the erythrocytes and circulates bound inside the erythrocytes.(22)
Little is known about the distribution of ondansetron in tissue. Animal data indicate a brainplasma ratio of less than 0.5,[22] suggesting that ondansetron penetrates into the central nervous system. In humans, the concentration of ondansetron in the cerebrospinal fluid is less than 15% of that measured in the plasma: in a study with 6 volunteers,(23) ondansetron concentrations ranged from 39.5 to 147 ~glL in plasma and from 2.6 to 15.4 ~glLin the cerebrospinal fluid, with good correlation between plasma and cerebrospinal fluid concentrations (r = 0.89, P = 0.017). Therefore, while ondansetron may penetrate the central nervous system, it does not do so very readily.l22,23) In young, healthy individuals, there are no significant
Clin. Pharmacokinet. 29 (2) 1995
Ondansetron Clinical Pharmacokinetics
differences between the distribution parameters of ondansetron for any of the dosage regimens investigated, and there is also no evidence of accumulation at steady-state.l3)
The degree of plasma protein binding of ondansetron is only 70 to 76%, and this is therefore not an important factor in the pharmacokinetic profile of the drug.[3) In addition, a-i-acid glycoprotein, a protein whose levels can increase markedly in cancer patients, is not a major binding protein for ondansetron.l22)
The enhanced bioavailability of ondansetron is the most significant difference found in cancer patients compared with healthy volunteers. Bioavailability in cancer patients averaged 85 to 87% (albeit with considerable interpatient variability), while in healthy individuals it ranged from approximately 50 to 70% (see section 3.3).[11)
3.3 Metabolism
Ondansetron is extensively metabolised by the Ii ver; figure 3 shows the metabolism of the drug in humans.[22)
Metabolism occurs primarily through oxidation, predominantly at the 8-position to produce 8-hydroxy-ondansetron (40% of the ondansetron administered is transformed into this metabolite) and to a lesser extent «20%) at the 7 -position to give 7-hydroxy-ondansetron. Less than 5% is metabolised by oxidation at the 6-position, producing 6-hydroxy-ondansetron. In addition, a very small amount of N-demethylalkylation occurs to give Ndemethyl-ondansetron. Sulphate and glucuronide conjugates are then formed from these intermediates.l22,24)
The 8-hydroxy-ondansetron metabolite has a potency equivalent to that ondansetron, while the other metabolites are less potent. Despite this, 8-hydroxy-ondansetron probably contributes little to the activity of the parent compound: none of the metabolites have been detected in plasma, probably because the active metabolites are rapidly further metabolised into glucoronide and sulphate conjugates before leaving the liver.l22)
Little is known about the enzymatic system involved in the biotransformation of ondansetron. A recent study[25) showed that cytochrome P450 (CYP2D6) is involved in the metabolism of ondansetron, which also appears to undergo CYP3A metabolism. Therefore, drug interaction with drugs that are hepatic enzyme inducers or inhibitors could potentially occur; however, specific data are lacking. For example, dexamethasone (a potent inducer of CYP3A) could lead to increased enzyme levels, and thus to increased ondansetron elimination, despite the fact that the combination of ondansetron with dexamethasone is more efficacious than ondansetron alone in preventing nausea and vomiting in patients treated with cisplatin.l I ,25) No pharmacokinetic data with respect to ondansetron are yet available for this combination.
There is no evidence of polymorphic metabolism of ondansetron. The pharmacokinetics of ondansetron following an 8mg intravenous dose has been investigated in 12 people previously phenotyped with debrisoquine (6 were poor metabolisers and 6 extensive metabolisers), to determine whether pharmacokinetics exhibit bimodality associated with genetic polymorphic control of metabolism. [26) No significant differences in the AVC, Cmax, plasma clearance (CL) or tl/ 2P were found between the poor and the extensive metabolisers. It was concluded that ondansetron clearance is not mediated exclusively by CYP2D6. Furthermore, despite a 4- to 5-fold range in ondansetron CL values measured in 86 young healthy male volunteers, there was no evidence of a bimodal or trimodal distribution of these values (fig. 4).l22)
3.4 Elimination
The hepatic oxidative metabolism accounts for more than 95% of ondansetron clearance from the body. Drug metabolites are excreted in the urine and faeces, with 44 to 53% being recovered in urine within 24 hours of administration.[7) Renal clearance accounts for less than 5% of total CL of unaltered ondansetron after intravenous administrationp,7)
Clin. Pharmacoklnet. 29 (2) 1995
102 Roila & Del Favero
Very minor N-Demethyl-ondansetron
Minor
HO
I CH3
Ondansetron Very minor 7 -Hydroxy-ondansetron -----,
t Minor
o
8-Hydroxy-ondansetron
Majo!
Glucuronide conjugate
\Major
Sulphate conjugate
HO
Glucuronide conjugate
?
6-Hydroxy-ondansetron
t? Sulphate conjugate
Fig. 3. Metabolism of ondansetron in humans: major, >20% of dose; minor, <20% of dose; very minor, <5% of dose (from Pritchard,I22) with permission). Symbol: ? indicates uncertainty about a metabolic pathway.
In healthy individuals, total CL ranges from approximately 420 to 845 mllmin (25 to 50.7 Lib); this is similar in cancer patients (16 to 32 Lib) and does not change significantly with method of administration. This value of CL is approximately 40% of total hepatic blood flow; only very large changes in hepatic blood flow would therefore be expected to result in significant changes in ondansetron clearance. [22] Renal clearance from
plasma has been estimated to be between 10 and 20 mllmin (0.6 and 1.2 LIb),I3,7]
CL has also been evaluated in cancer patients who received escalating or repeated doses of ondansetron,[12] administered as a IS-minute loading infusion of 8, 10 or 12mg, followed by a 24-hour infusion of 1, 2 or 4 mglb, respectively.[12] AUC values did not correlate with CL, an observation suggestive of nonlinear pharmacokinetics. In
Fig. 4. Frequency histogram of ondansetron plasma clearance in 86 young healthy male volunteers (from Pritchard,I22] with permission).
fact, comparing the lowest and the highest doses, a proportional increase in concentration was not seen (see section 3.1), and CL values increased with increasing doses. A slightly prolonged V/2~ in cancer patients has been reported by some investigators,[II] but not by others.l lO]
Repeated doses of ondansetron for 4 days does not appear to result in any change in CL of ondansetron, and might indicate that ondansetron does not inhibit or accentuate its own metabolism. However, 4 days of treatment is too short a period in which to evaluate the induction of hepatic drug metabolism (which usually requires about 2 weeks before the maximum effect is attained).
Some studies have demonstrated decreased CL values and greater oral bioavailability of ondansetron in cancer patients than in healthy young individuals.£? ,I a,ll] These data are difficult to interpret due to the many factors which may influence the CL of ondansetron (see section 4).
4. Factors Affecting Ondansetron Pharmacokinetics
4.1 Age
Two studies, both carried out in healthy individuals, have evaluated the effect of advanced age on ondansetron pharmacokinetics.l9,13]
In one study,[9] 32 healthy male volunteers (16 aged 18 to 40 years and 16 aged over 65 years) participated in a randomised, crossover study evaluating a single 8mg dose of ondansetron as either an oral tablet or a 15-minute intravenous infusion. A significant reduction in CL was observed in the elderly group compared with the younger group. In addition, the volume of distribution at steadystate (Vss) was greater in the elderly than in the young group. The combined result of these changes was a 56% increase in the mean terminal t\W of ondansetron in the elderly compared with the young group (tV2~ increased from 3.2 to 5 hours with intravenous administration and from 3.1 to 5.0 hours with oral administration) [table 1].[9] The reduction in nonrenal clearance also led to an increase in the absolute oral bioavailability of ondansetron in the elderly, presumably as a result of decreasing first-pass metabolism. The results of this study are consistent with a reduction in hepatic function in the elderly.
The other study[13] evaluated the pharmacokinetics of the same doses of ondansetron (8mg as oral tablet or 15-minute intravenous infusion) in 34 healthy volunteers placed in 1 of 3 groups according to age and gender (age groups were 21 to 38 years, 61 to 74 years and 75 to 82 years). Ageinduced modifications of pharmacokinetic param-
Clin. Pharmacokinet. 29 (2) 1995
104
eters were similar after the intravenous or oral dose. Cmax and AVC values gradually increased and mean CL steadily decreased with increasing age. In contrast to the results of the previous study, V ss was unaffected by age. However, increases in mean plasma tY213 (3.3, 4.5 and 5.4 hours, respectively) and mean absolute bioavailability (57%, 61 % and 69%, respectively) with increasing age were again found (table 1).[6,13]
The most clinically relevant consequence of reduced CL of ondansetron in elderly people would appear to be greater drug accumulation with repeated administration of ondansetron (using the same regimen as for younger individuals). However, because of the great variability in CL and tY213 values between individuals in the same age group, there is considerable overlap of individual values across groups.l13] Therefore, it is not reasonable to adjust the dosage regimen solely on the basis of age without clinical evidence of inadequate efficacy or dose-limiting toxicity. [27]
Two studies have evaluated ondansetron pharmacokinetics in paediatric patients. In one study, 21 children scheduled for surgery received an intravenous dose of ondansetron (2mg for those aged 3 to 7 years, and 4mg for those aged 8 to 12 years) before induction of anaesthesia. Cmax values in both age groups were similar to those reported in adults after a dose of 0.15 mg/kg. The mean clearance of ondansetron was greater in the younger age groups than in the older age groups [164 vs 120 ml/min (9.84 vs 7.2 L/h)], while Vss was not affected by age on a per-kilogram basis.[28] In the other study, carried out with 21 children administered ondansetron 0.15 mg/kg x 3 doses every 4 hours to prevent chemotherapy-induced emesis, tY213 was slightly shorter in those aged 4 to 12 years and those with acute lymphocytic leukaemia than in older (13 to 18 years of age) patients (2.5 vs 3.8 hours, respectively),l29]
4.2 Gender
There is some evidence from one study that gender may be a factor in determining ondansetron disposition.[13] This study showed that after a sin-
gle intravenous dose of ondansetron 0.15 mg/kg, mean CL was significantly lower in female volunteers than in male volunteers in all age groups (young, 21 to 38 years old; elderly, 61 to 74 years old; old, 75 to 82 years old). No differences between the sexes was observed for Cmax or tmax values. The difference in CL was slightly less apparent, albeit still statistically significant, if CL was normalised for body weight. However, weightnormalised Vss was also slightly but significantly lower in female volunteers, and therefore, no change in plasma v/213 between sexes was observed.
However, after a single 8mg oral dose of onansetron, both Cmax and AVC were significantly higher in female than in male participants, primarily because of the higher absolute bioavailability of ondansetron in female participants of all ages. The difference varied from 48% (male) and 66% (female) in the young group to 62% (male) and 75% (female) in the old group. The greater systemic availability of ondansetron found in women may be due to a combination of various factors, such as slower clearance, higher ondansetron bioavailability (presumably because of reduced first-pass metabolism) and smaller apparent V d in comparison with males. Although these differences may be significant in pharmacokinetic terms, they might be clinically insignificant or only require dosage adjustments in patients receiving repeated oral doses of ondansetron for a relatively long term period.l6,13]
4.3 Hepatic Impairment
The pharmacokinetics of ondansetron in patients with impaired liver function has been investigated in two studies.[30,31]
In one study, the pharmacokinetic parameters of ondansetron (a single 8mg intravenous dose) were studied in a group of patients with varying degrees of hepatic impairment, in comparison with a control group of healthy individuals.[30]24 people took part in the study. The patients were stratified for hepatic impairment, using the Pugh system,[30] as being mildly impaired (5 men and 1 woman, aged 30 to 52 years), moderately impaired (4 men and 2
Clin. Pharmacokinet. 29 (2) 1995
Ondansetron Clinical Pharmacokinetics
women, aged41 to 76 years) and severely impaired (2 men and 4 women, aged 33 to 75 years). The control group consisted of 4 men and 2 women aged between 19 and 23 years.
Evaluation of the pharmacokinetic parameters determined showed marked differences between the healthy individuals and the patients. Patients with severe hepatic impairment had lower mean CL [96 vs 478 mllmin (5.76 vs 28.68 L/h)] and increased AUC (1383 vs 279 IlglL. h) and t'l2~ (21 vs 3.6 hours) values compared with the control group. These differences were all statistically significant (p < 0.01). The corresponding values for patients with moderate hepatic impairment fell between these extremes. V ss was greater in all patient groups than in the control group, but the magnitude of the change was not statistically significant in any patient group and did not correlate with increasing severity of hepatic impairment. No significant changes in Cmax were found.
The other study analysed ondansetron pharmacokinetics in 12 patients with chronic liver disease, categorised (4 patients in each category) according to liver impairment as in the above study, and ageand gender-matched to the same number of healthy individuals. Ondansetron 8mg was administered orally or intravenouslyJ31]
As in the first study, patients with mild to moderate hepatic impairment exhibited CL of approximately 50% of that seen in the control group. In patients with severe hepatic impairment, CL was reduced to about 35% of the control value. Liver disease did not significantly alter the Vd of ondansetron. Plasma V/2~ was extended to 10 to 13 hours in the mild to moderate impairment group and to 20 hours in the severe impairment group, compared with 6 hours in the healthy control group. Bioavailability of oral ondansetron increased from 60% in the control group to 80% in the mild to moderate impairment group and to 98% in the severe impairment group.
As expected for a drug which is cleared predominantly by hepatic metabolism, these studies indicated marked changes in CL and bioavailability of ondansetron associated with severe liver function
impairment. These changes in CL are probably mainly related to a decrease in intrinsic hepatic metabolic function. Changes in hepatic blood flow seem to be unlikely to have an effect. [32] In the first study, the patient group was older than the control group; this may have contributed further to the reduction in CL (see section 4.1).[30] The increased bioavailability of ondansetron found in the second study is probably due to decreased first-pass metabolism of the drug.[31]
On the basis of these results, it seems sensible to suggest that frequency of ondansetron administration should be limited to once per day, and that these daily doses should not exceed 8mg in patients with severe hepatic impairment.
4.4 Renal Impairment
It is unlikely that renal dysfunction would significantly alter the pharmacokinetics of ondansetron because renal clearance accounts for less than 5% of total CL; however, no pharmacokinetic studies have been carried out in patients with renal impairment.
4.5 Chemotherapy
In most clinical situations, ondansetron is used concurrently with antineoplastic agents; it is therefore important to know the possible effect of cancer chemotherapy on the pharmacokinetic profile of ondansetron.
To properly evaluate possible drug-induced changes, it would be necessary to compare the pharmacokinetic parameters of ondansetron before and during concurrent chemotherapy. Unfortunately, only one study to date has been carried out according to this design, evaluating the effects of a 5-day course of chemotherapy with cisplatin and fluorouracil on the pharmacokinetics of oral ondansetron 8mg.[I1] In this study, the pharmacokinetic parameters of 20 patients after an 8mg oral dose of ondansetron were determined before chemotherapy (day 1) or after chemotherapy (day 5). The results are given in table IV.
Although average AUC values did not change significantly from day 1 to day 5, patients with
Clin. Pharmacokinet. 29 (2) 1995
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Table IV. Pharmacokinetic parameters (mean ± standard deviation) of ondansetron concurrent with chemotherapyllli
Parameter Day 1 of Day 50f chemotherapy chemotherapy
Abbreviations: AUC = area under the concentration-time curve from time 0 to infinity; Cm_x = peak plasma drug concentration; tm_x = time to Cm_x; \1;.,~ = elimination half-life.
AUC values greater than 600 ~g/L· h on day I showed dramatic changes in AUC on day 5, indicating that CL of ondansetron may have changed significantly in these patients during the 5-day study period. The cause of such changes in AUC in some patients is unknown.
In summary, this study showed that chemotherapy with cisplatin and fluorouracil did not significantly alter the pharmacokinetics of oral ondansetron in cancer patients during 5 days of treatment. Further, indirect, support for this finding comes from the results of a previous study which found similar AUC values on day 1 and day 4 of cisplatin administration after intravenous infusion of ondansetron.l JO]
Little attention has been given to date to the possibility of effects of ondansetron on the pharmacokinetics of cancer chemotherapeutic agents.
4.6 Route and Time of Administration
The pharmacokinetics of oral, intravenous, intramuscular, subcutaneous and rectally administered formulations are discussed in section 3.1.
Time of administration has also been studied. Circadian variations in the pharmacokinetics of ondansetron have been reported in 24 young healthy male volunteers receiving 8mg tablets 3 times a day (0700h, 1500h, 2300h) for 9 doses.[33] The steady-state AUC was highest following the morning dose, declining by 15% by the night-time dose, with Cmax becoming significantly lower and tmax more prolonged as the day progressed. These
changes in pharmacokinetics of ondansetron may reflect diurnal variations in hepatic metabolism and gastric motility.
4,7 General Anaesthesia
Very limited data are available on ondansetron pharmacokinetics in patients undergoing general anaesthesia. The pharmacokinetics of oral ondansetron (16mg) have been investigated in 8 patients (mean age 44 years, range 27 to 58 years) undergoing anaesthesia for cholecystectomy or hysterectomy.[6] Ondansetron was administered 1 hour before anaesthesia, during premedication with oral diazepam or temazepam. Anaesthesia was induced with intravenous thiopental sodium and maintained with inhaled nitrous oxide in oxygen. Analgesia during anaesthesia was provided by intravenous fentanyl, and muscle relaxation by atracurium besilate or alcuronium; postoperative analgesia was provided by intravenous morphine.
The pharmacokinetics of ondansetron were not affected by the premedicants or during the surgical procedure. However, postoperatively the elimination of ondansetron was prolonged (mean tY2P 5.6 hours). Although all patients received morphine, it was thought to be unlikely that morphine was the cause of this phenomenon.[6] A more probable explanation involves the changes in metabolism, blood flow and Vd frequently observed after surgery.
These data suggest that dosage adjustment is not required in patients undergoing general anaesthesia.
5. Pharmacokinetic-Pharmacodynamic Relationship
Several studies have attempted to ascertain the pharmacokinetic parameters related to the clinical efficacy of ondansetron.[JO,12,14,29,34-36] Unfortu-nately, the results are conflicting, and fail to conclusively demonstrate any direct pharmacokineticpharmacodynamic relationship or to identify with certainty a plasma concentration level below which treatment fails.
Fig. 5. Exposure-response relationship with ondansetron (from Pritchard,[22] with permission).
Four studies indicate that control of emesis may be related to systemic availability of ondansetron, as ascertained by measuring the AVC or the 4-hour (trough levels) plasma concentrations of on dan setron) 10, 14,29,36] In these studies, patients with higher AVC values or a high 4-hour plasma concentration had a greater likelihood of complete protection against emesis than those who had a lower exposure to ondansetron. Moreover, one study showed that the higher the emetogenic stimulus, the greater the amount of systemically availabile ondansetron required to achieve the same level of control (fig. 5);[36] i.e., the dose exposure-response curve is shifted to the right in the presence of the greater stimulus. These data are consistent with a receptorbased mechanism for ondansetron activity, and are also supported by studies in animal models,l37]
None of the other studies reviewed demonstrated a relationship between any pharmacokinetic parameter and therapeutic success, suggesting that plasma concentrations do not correlate with tissue concentrations or the amount of drug bound to receptor sites)12,34,35]
The reason for these conflicting results may be because these studies are open to 2 major criticisms: first, most of them are too small for a mean-
ingful statistical evaluation of exposure to response relationship; and secondly, the number of blood samples collected in these studies during treatment was often inadequate. These drawbacks have a practical consequence: uncertainty about the optimal dose of the currently recommended ondansetron regimens.
Recently, 3 large, double-blind studies have reevaluated the optimal dose and schedule of intravenous ondansetron,l38-40] In two of these, a single 32mg dose of ondansetron administered before cisplatin (50 to 120 mg/m2) showed a similar efficacy and toxicity with respect to an 8mg loading dose of ondansetron followed by a 24-hour infusion of 1 mg/h,l38,39] One of these studies,[39] involving 535 patients, included a third arm in which patients received only a single 8mg intravenous dose of ondansetron before cisplatin chemotherapy. Control of emesis was similar in all 3 treatment groups, with complete protection from vomiting in about 55% of patients. However, these results were not confirmed in another study evaluating 699 patients . In fact, the efficacy of an 8mg intravenous single dose of ondansetron and that of ondansetron 0.15 mg/kg every 4 hours for 3 doses was shown to be inferior to a 32mg intravenous single dose)40] Unfortunately, pharmacokinetic data are not available from these trials. Further studies are therefore needed to better define the pharmacokinetic-pharmacodynamic relationship of ondansetron, as well as the optimal dose and schedule of administration.
6. Conclusions
Ondansetron is an effective and well tolerated drug which has substantially improved our control of chemotherapy-induced emesis. Despite some limitations in the studies reviewed, sufficient information is available on the main pharmacokinetic characteristics of ondansetron to suggest guidelines for rational use of the drug.
If preliminary data are confirmed, then intramuscular, subcutaneous and rectal administration as well as controlled-release formulations are possible alternative methods to oral and intravenous administration of ondansetron in some patients.
Clin. Pharmacoklnet. 29 (2) 1995
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Whether control of emesis is related to systemic availability of ondansetron is still a matter of debate; further studies are required to clarify this point. In consequence, the optimal dose and schedule of ondansetron is still to be identified with certainty.
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38. Marty M, d' Aliens H, et Ie Groupe Multicentrique Francais: etude randomisee en double-insu comparant I' efficacite de I' ondansetron selon deux modes d ' administration: injection unique et perfusion continue. Cahiers Cancer 1990; 2: 541-6
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40. Beck TM, Hesketh PJ, Madajewicz S, et al. Stratified, randomized, double-blind comparison of intravenous ondansetron administered as a multiple-dose regimen versus two singledose regimens in the prevention of cisplatin-induced nausea and vomiting. J Clin Oncol 1992; 10: 1969-75
Correspondence and reprints: Dr Fausto Roila, Medical Oncology Division, Policlinico Hospital, 06122 Perugia, Italy.
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Mathematical Modelling of Pharmacokinetic Data
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