PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of aacPermissionsJournals.ASM.orgJournalAAC ArticleJournal InfoAuthorsReviewers
 
Antimicrob Agents Chemother. 2007 August; 51(8): 2943–2947.
Published online 2007 January 22. doi:  10.1128/AAC.01013-06
PMCID: PMC1932547

Effect of Lamivudine on the Plasma and Intracellular Pharmacokinetics of Apricitabine, a Novel Nucleoside Reverse Transcriptase Inhibitor, in Healthy Volunteers[down-pointing small open triangle]

Abstract

Apricitabine is a novel deoxycytidine analog reverse transcriptase inhibitor. In vitro apricitabine competes with other deoxycytidine analogues for intracellular phosphorylation mediated by deoxycytidine kinase. The topic of this study, the effect of concomitant administration of apricitabine and lamivudine on the plasma and intracellular pharmacokinetics of the two compounds, was investigated in healthy volunteers. Participants (n = 21; age, 18 to 30 years) received apricitabine at 600 mg twice daily, lamivudine at 300 mg once daily, and the two treatments in combination for 4 days each in random order. Plasma, urine, and intracellular pharmacokinetics were assessed on day 4 of each treatment period. Apricitabine was rapidly absorbed after oral administration, with peak concentrations being attained after a mean of 1.76 h. Coadministration with lamivudine had no significant effect on the plasma and urine pharmacokinetics of apricitabine. However, the formation of apricitabine triphosphate in peripheral blood mononuclear cells was markedly reduced after the coadministration of apricitabine and lamivudine than after the administration of apricitabine alone: the area under the concentration-time curve from 0 to 12 h for apricitabine triphosphate during combination treatment was ca. 15% of that seen after the administration of apricitabine alone. In contrast, apricitabine had no effect on the plasma pharmacokinetics of lamivudine or on the formation of lamivudine triphosphate in peripheral blood mononuclear cells. These results are consistent with in vitro findings that lamivudine inhibits the intracellular phosphorylation of apricitabine. In conjunction with similar in vitro observations for emtricitabine and apricitabine, these results suggest that apricitabine should not be coadministered with other deoxycytidine analogues for the treatment of human immunodeficiency virus infection.

Nucleoside reverse transcriptase inhibitors (NRTIs) have a central place in highly active antiretroviral therapy (HAART) regimens for the treatment of human immunodeficiency virus (HIV) infection, and the use of these agents is recommended in current HIV management guidelines (13). However, the development of viral resistance during HAART and the emergence of drug-resistant strains of HIV type 1 (HIV-1) represent significant clinical challenges, necessitating the development of new agents and regimens for the control of HIV infection (3). This in turn will require an understanding of the complex pharmacological and pharmacokinetic interactions between antiretroviral drugs of the same or different classes.

The potential importance of such interactions is underlined by the experience with combinations of thymidine analog NRTIs. Since NRTIs are activated by common intracellular phosphorylation pathways (14), they are potentially susceptible to interactions with other analogs of the same nucleotide base. For example, in in vitro studies, coincubation of zidovudine (AZT) and stavudine results in decreased formation of stavudine triphosphate, whereas phosphorylation of AZT is unimpaired (7-10). This interaction is believed to be responsible for the poor clinical efficacy of combination therapy with AZT and stavudine (6, 14).

Apricitabine [(−)2′-deoxy-3′-oxa-4′-thiocytidine; formerly known as BCH10618, SPD754, and AVX754] is a novel deoxycytidine analog that is under development for the treatment of HIV infection. Although this agent has a similar structure to lamivudine and the fluorinated derivative emtricitabine, it has been shown to retain antiretroviral activity against lamivudine-resistant clinical isolates and laboratory strains of HIV-1 (2). Apricitabine also retains a high level of activity against zidovudine-resistant strains; in in vitro studies, the addition of up to five thymidine-associated mutations conferred a median reduction in susceptibility of only 1.8-fold (2). The first stage in the intracellular activation of apricitabine, the formation of apricitabine monophosphate, requires the enzyme deoxycytidine kinase (5), which is also responsible for the phosphorylation of lamivudine and emtricitabine. There is thus a potential for pharmacokinetic interactions when these agents are administered concurrently. Hence, the present study was undertaken to investigate the plasma and intracellular pharmacokinetics of apricitabine and lamivudine when administered separately or in combination in healthy volunteers.

MATERIALS AND METHODS

This study was an open-label, randomized, three-way crossover study performed at a single center in the United Kingdom. It was conducted according to the principles of the Declaration of Helsinki and Good Clinical Practice and was approved by the local Ethics Committee. All participants were enrolled in January 2003, and the study was completed in February 2003.

Participants.

Healthy male HIV-negative volunteers, aged between 18 and 40 years, were enrolled in the study. All participants were between 65 and 90 kg in weight and were within 15% of their ideal weight for height and frame. Men with significant medical or psychiatric conditions or a history of substance abuse were excluded from the trial. Other exclusion criteria were (i) the use of prescription medication within 14 days or of over-the-counter medication within 7 days prior to the study; (ii) allergy or intolerance to the study medication; (iii) blood or plasma donation within 90 days prior to the study; (iv) smoking; and (v) the presence of hepatitis B surface antigen or hepatitis C antibody at screening. Written informed consent was obtained from all participants before inclusion in the study.

Study design.

All participants received in random order apricitabine (600 mg twice daily [12 h between doses]), lamivudine (300 mg once daily in the morning), and the two treatments in combination. Each treatment was given for 4 days, with washout periods of at least 7 days between treatments, and pharmacokinetic analysis was performed as described below on day 4 of each period. Randomization was performed in blocks by means of a computer generated schedule (PROC PLAN version 6.12).

All treatments were given with 240 ml of water. Meals were given at standardized times except on day 4, when the morning dose was given after an overnight fast of at least 10 h, and participants were not allowed to eat until at least 2 h after dosing. Participants were requested to abstain from alcohol, grapefruit, caffeine, or xanthine and from strenuous physical exercise from 48 h before treatment to the end of the treatment period.

Blood and urine sampling and analysis.

Blood samples (4.9 ml) were obtained via an indwelling cannula before the morning dose on day 4, and at 0.5, 1, 1.5, 2, 4, 8, 12, 13, 14, 18, 24, and 36 h after dosing. Plasma was separated by centrifugation and stored at −20°C prior to analysis. In addition, peripheral blood mononuclear cells (PBMC) were obtained from further samples (6 ml) collected at 2, 4, 8, 12, and 24 h after dosing. PBMC from triplicate samples were obtained by density gradient centrifugation and resuspended in 1 ml of phosphate-buffered saline. The cells were centrifuged and resuspended in 0.6 ml of 70/30 (vol/vol) methanol-Tris-HCl buffer (pH 7.4).

Participants emptied their bladders before dosing on day 4, and urine was collected over 0 to 4 h, 4 to 8 h, 8 to 12 h, 12 to 24 h, and 24 to 36 h after dosing. The volume of each collection was recorded, and duplicate 50-ml samples were stored at −20°C before analysis.

The concentrations of apricitabine and lamivudine in plasma or urine were measured by a validated high-performance liquid chromatography (HPLC) technique as described previously (2a).

Concentrations of apricitabine and lamivudine triphosphates in PBMC were measured by HPLC after enzymatic digestion with 4.7 U of alkaline phosphatase. Calibration standards and quality control samples were prepared by spiking the appropriate analyte into PBMC extract lysate such that the sample contained the equivalent of approximately 3.6 × 107 cells/ml. The internal standard consisted of 20 μl of a 1-μg/ml concentration of [13C2-15N3]apricitabine triphosphate. Standards, samples, and blanks were extracted by anion exchange on Waters Accell QMA 96-well solid-phase extraction plates. The plates were then successively washed with 1 ml each of 55, 75, and 95 mM KCl, followed by 2 ml of 125 mM KCl, in order to remove apricitabine, lamivudine, and their respective mono- and diphosphates. The triphosphates were eluted from the plates with 1.5 ml of 500 mM KCl and collected into wells containing 0.1 ml of a 25-U/ml concentration of alkaline phosphatase. These plates were then incubated at 37°C in order to dephosphorylate the triphosphates. The hydrolyzed samples were washed with 1.5 ml of water on a Varian C18 96-well solid-phase extraction plate and eluted with 0.7 ml of 50/50 (vol/vol) methanol-acetonitrile. The eluants were dried under nitrogen at 55°C, reconstituted in 0.1 ml of water, and centrifuged at 4,000 rpm for 10 min. The HPLC system consisted of a Leap CTC A200SE autosampler and a Perkin-Elmer Series 200 liquid chromatograph with a YMC ODS AQ C18 column (2 by 100 mm) interfaced to a PE Sciex API 3000 mass spectrometer. Samples (20 to 40 μl) were injected onto the column and eluted with a gradient of 0.2% formic acid in acetonitrile (A) and 0.2% formic acid in 50/50 (vol/vol) water-methanol (B). The elution profile consisted of a linear gradient from 100% A to 100% B over 4.2 min, followed by a linear gradient back to 100% A over 1 min: the flow rate during this procedure ranged from 0.4 to 0.6 ml. Analytes were detected by positive ion electrospray tandem mass spectrometry in multiple reaction monitoring mode. The transitions mz 230→112 and 235→117 were monitored from apricitabine or lamivudine and the internal standard, respectively. All results were calculated by using a weighted linear regression of the standard curve [1/(concentration)2].

A minimum yield of 3.6 × 107 cells from 18 ml of blood permitted a lower limit of quantification of at least 0.0592 pmol/106 cells. The assay was validated over the range 1 to 1,000 ng/ml of lysate (equivalent to ca. 0.0592 to 59.2 pmol/106 cells). The mean accuracy (bias) and precision (expressed as the coefficient of variation) for calibration standards ranged from 2 to 4% and 4.3 to 7.5%, respectively, for apricitabine triphosphate: for lamivudine triphosphate the mean bias was 2% across the calibration range, while precision ranged from 5.6 to10.1%. The mean accuracy and precision for quality control samples were similar (inter-run, apricitabine triphosphate [2.3 to 3.3% and ≤4.1 to 5.1%] and lamivudine triphosphate [2.0 to 5.1% and ≤4.1 to 8.5%]; intra-run, apricitabine triphosphate [−3.0 to 2.8% and ≤1.8 to 3.3%] and lamivudine triphosphate [−6.3 to 5.2% and ≤1.6 to 4.3%]). Specificity assessments showed that the determination of apricitabine triphosphate and lamivudine triphosphate was not affected by the presence of apricitabine, lamivudine, or their respective mono- or diphosphates.

Pharmacokinetic and statistical analysis.

The pharmacokinetic parameters of apricitabine and lamivudine in plasma and urine and of apricitabine and lamivudine triphosphates in PBMC were calculated by noncompartmental techniques using WinNonLin software (version 4.0; Pharsight Corp., Mountain View, CA). The principal parameters measured were the peak plasma or PBMC concentrations (Cmax); time to peak concentrations (Tmax; both derived by visual inspection of the concentration-time curves); area under the concentration-time curve (AUC) from 0 to 12, 12 to 24, and 0 to 24 h; apparent total oral clearance (CLT/F; calculated as dose divided by the AUC for a given time interval [AUC0-τ]); renal clearance (CLR; calculated as the amount excreted in urine over 24 h divided by the plasma AUC0-24); steady-state volume of distribution (Vz/F; calculated as dose/λz.AUC0-τ, where λz is the terminal elimination rate constant); and the apparent terminal half-life [t1/2z; calculated as ln(2)/λz].

The pharmacokinetic populations for apricitabine and lamivudine consisted of all participants who received at least one dose of the appropriate medication and for whom sufficient data were available to determine at least the plasma Cmax and AUC0-τ. The sample size was based on experience from a previous study with apricitabine, which suggested that the within-subject-between-treatment variance of apricitabine concentrations was ca. 0.11, assuming that the true AUC of apricitabine in the presence of lamivudine was within 85% of that for apricitabine when taken alone. From this, it was calculated that a sample size of 18 participants would provide 80% power to reject the null hypothesis of inequivalence, with a significance level of 0.05.

RESULTS

A total of 21 healthy male volunteers entered the study, all of whom completed all three treatment periods. Their mean (± the standard deviation) age was 24.2 ± 3 years (range, 18 to 30 years), their mean weight was 76.8 ± 6.02 kg (range, 70.8 to 87.1 kg), and their mean height was 1.79 ± 0.07 m (range, 1.65 to 1.93 m). All participants were evaluable for both pharmacokinetics and safety.

Apricitabine pharmacokinetics.

The plasma concentrations of apricitabine, when administered alone and concomitantly with lamivudine, are shown in Fig. Fig.1A,1A, and the pharmacokinetic parameters in plasma and urine are summarized in Table Table1.1. Apricitabine was rapidly absorbed after oral administration, with peak concentrations being attained after a mean of 1.76 h. The mean elimination half-life was ca. 2.6 h, and the renal clearance was approximately 12 liters/h. Visual inspection of the plasma concentration-time profiles obtained 12 and 24 h after the morning dose on day 4 showed that steady-state concentrations had been achieved by this time. Coadministration with lamivudine had no significant effect on the plasma and urine pharmacokinetics of apricitabine. The ratio of the geometric mean Cmax for apricitabine alone and in the presence of lamivudine was 0.987, with a 90% confidence interval (CI) of 0.871 to 1.12. The corresponding ratio for AUC0-24 was 0.924, with a 90% CI of 0.874 to 0.977.

FIG. 1.
(A) Plasma concentrations of apricitabine after oral administration of 600 mg twice daily alone or in combination with lamivudine at 300 mg once daily. Treatment was given for 4 days, and plasma concentrations were measured after the morning dose on day ...
TABLE 1.
Pharmacokinetic parameters of apricitabine in plasma after oral administration of 600 mg twice daily alone or in combination with lamivudine at 300 mg once daily for 4 days

Intracellular concentrations of apricitabine triphosphate after oral administration of apricitabine alone or concomitantly with lamivudine are shown in Fig. Fig.1B,1B, and the corresponding pharmacokinetic parameters are summarized in Table Table2.2. In contrast to the plasma and urine pharmacokinetics of apricitabine, concurrent administration of lamivudine had a marked effect on the intracellular pharmacokinetics of apricitabine triphosphate. AUC0-12 values in the presence of lamivudine were only ca. 15% of those seen when apricitabine was administered alone. The half-life of apricitabine triphosphate was approximately 6 h when apricitabine was administered alone and 5 h when the parent drug was administered with lamivudine. However, the limited duration of sampling means that these data should be interpreted with caution (see footnote to Table Table2).2). The observed minimum concentrations of apricitabine triphosphate (Cmin) in PBMC after concomitant administration of lamivudine were ca. 13% of those seen after administration of apricitabine alone; however, neither the Cmax/Cmin ratio nor Tmax appeared to be affected by lamivudine.

TABLE 2.
Pharmacokinetic parameters of intracellular apricitabine triphosphate in PBMC after oral administration of apricitabine at 600 mg twice daily alone or with lamivudine at 300 mg once daily for 4 days

Lamivudine pharmacokinetics.

Plasma concentration-time profiles for lamivudine, alone and in the presence of apricitabine, are shown in Fig. Fig.2A,2A, and pharmacokinetic parameters in plasma and urine are summarized in Table Table3.3. Lamivudine was readily absorbed after oral administration, with peak plasma concentrations being attained after approximately 1 h. The mean half-life was ca. 4.5 μg/ml, and renal clearance was 13 to 14 liters/h, a value similar to that previously reported in healthy volunteers (12). Coadministration of apricitabine had no significant effect on the plasma or urine pharmacokinetics of lamivudine. The ratio of the geometric mean Cmax of lamivudine alone or in the presence of apricitabine was 0.972, with a 90% CI of 0.876 to 1.08. The corresponding ratio for AUC0-24 was 0.995, with a 90% CI of 0.945 to 1.05.

FIG. 2.
(A) Plasma concentrations of lamivudine after treatment for 4 days with lamivudine at 300 mg once daily alone or in combination with apricitabine at 600 mg twice daily. (B) Concentrations of lamivudine triphosphate in PBMC after treatment for 4 days with ...
TABLE 3.
Pharmacokinetic parameters of lamivudine after oral administration of 300 mg once daily alone or in combination with apricitabine at 600 mg twice daily for 4 days

Intracellular concentrations of lamivudine triphosphate in PBMC are shown in Fig. Fig.2B,2B, and the corresponding pharmacokinetic parameters summarized in Table Table4.4. Concomitant administration of apricitabine had no effect on the intracellular concentrations or pharmacokinetics of lamivudine triphosphate.

TABLE 4.
Pharmacokinetic parameters of intracellular lamivudine triphosphate in PBMC after oral administration of lamivudine at 300 mg once daily alone or in combination with apricitabine at 600 mg twice daily for 4 days

DISCUSSION

Given the central place of NRTIs in HAART regimens (13), it can be anticipated that these agents will continue be used in combination in the management of HIV infection. Since the NRTIs are activated by common intracellular pathways (14), the potential for interactions between agents of the same or different classes must be carefully considered. The results of the present study suggest that a one-way interaction exists between apricitabine and lamivudine. In the presence of lamivudine, the formation of apricitabine triphosphate is reduced to ca. 15% of that seen when apricitabine was administered alone, whereas apricitabine had no effect on the intracellular pharmacokinetics of lamivudine triphosphate. This suggests that the antiretroviral efficacy of apricitabine is likely to be reduced when the drug is coadministered with lamivudine.

The results of the present study are consistent with an earlier in vitro study (11), in which 2′deoxycytidine, the natural substrate for deoxycytidine kinase, was shown to inhibit the phosphorylation of dideoxynucleoside analogues. Since deoxycytidine kinase is the enzyme responsible for the initial phosphorylation of both apricitabine and lamivudine (5, 14), competition between dideoxynucleosides for this enzyme is the most likely basis for the interaction observed in the present study. This would be consistent with the finding that ca. 20% of apricitabine in PBMC remains as unchanged drug compared to ca. 3% for lamivudine (5), which suggests that apricitabine may be a less efficient substrate for deoxycytidine kinase than lamivudine. Support for this hypothesis comes from the finding of a similar interaction to that reported here between lamivudine and zalcitabine, which is known to be a poor substrate for deoxycytidine kinase (1a, 11): lamivudine inhibits the formation of zalcitabine triphosphate, whereas zalcitabine has no effect on the phosphorylation of lamivudine (9, 16). The potential clinical importance of such interactions is highlighted by the recent finding that the antiretroviral activity of the developmental deoxycytidine analog dexelvucitabine is significantly reduced in the presence of lamivudine or emtricitabine (4a). The combination of zidovudine and stavudine has also been shown to have poor clinical efficacy (6), probably due at least in part to inhibition of thymidine kinase by zidovudine (14).

The finding that lamivudine apparently inhibits the intracellular activation of apricitabine both in vitro and in vivo appears to be at variance with a previous in vitro report (15) that the two agents have additive or synergistic activity against wild-type strains of HIV-1. However, in the latter study the antiretroviral activity of lamivudine was considerably higher than that of apricitabine. Thus, at similar concentrations of the two agents, the greater antiretroviral effect of lamivudine will overshadow the contribution of apricitabine and mask any inhibition of the latter's activity. In contrast, low concentrations of lamivudine would produce only a slight inhibition of apricitabine phosphorylation, and therefore this would also tend to obscure any potential antagonistic effect of lamivudine upon the activity of apricitabine.

In conjunction, these observations suggest that the efficacy of any combination of apricitabine and other deoxycytidine analogues is likely to be compromised as a result of this type of phosphorylation interaction. In vitro some of the effects of this interaction could be overcome by increasing the exposure to apricitabine. In patients receiving apricitabine monotherapy, exposure to intracellular apricitabine-triphosphate was related closely to parent concentrations in the plasma (1). However, when considering the dose-response relationship for observed across the range of apricitabine doses from 200 mg to 800 mg twice daily (4), it seems unlikely that clinical doses will be sufficient to overcome the interaction. Any such approach would therefore require careful clinical evaluation in patients with HIV before these combinations could be considered for routine clinical practice.

Apricitabine and lamivudine were well tolerated in the present study, both when given individually and in combination. No differences between the adverse events profiles of the three treatments were observed, and no safety issues were identified that might indicate grounds for concern during combination therapy with apricitabine and lamivudine.

In conclusion, the results of the present study in healthy volunteers suggest that concomitant administration of apricitabine and lamivudine may result in a reduction in the antiretroviral effect of apricitabine due to inhibition of intracellular phosphorylation. Therefore, apricitabine should not be coadministered with lamivudine, emtricitabine, or other deoxycytidine analogues used for the treatment of HIV infection.

Acknowledgments

We thank M. Shaw of Prism Ideas, Ltd., for his assistance in the generation of the manuscript and John Adams, who conducted the analysis of the pharmacokinetic data.

Footnotes

[down-pointing small open triangle]Published ahead of print on 22 January 2007.

REFERENCES

1. Adams, J., J. Sawyer, and L. Shiveley. 2004. Abstr. 11th Conf. Retrovir. Opportunistic Infect., abstr. 599.
1a. Balzarini, J., D. A. Cooney, M. Dalal, G. J. Kang, J. E. Cupp, E. DeClercq, S. Broder, and D. G. Johns. 1987. 2′,3′-Dideoxycytidine: regulation of its metabolism and anti-retroviral potency by natural pyrimidine nucleosides and by inhibitors of pyrimidine nucleotide synthesis. Mol. Pharmacol. 32:798-806. [PubMed]
2. Bethell, R. C., Y. S. Lie, and N. T. Parkin. 2005. In vitro activity of SPD754, a new deoxycytidine nucleoside reverse transcriptase inhibitor (NRTI), against 215 HIV-1 isolates resistant to other NRTIs. Antivir. Chem. Chemother. 16:295-302. [PubMed]
2a. Bethell, R., J. De Muys, J. Lippens, A. Richard, B. Hamelin, C. Ren, and P. Collins. 2007. In vitro interactions between apricitabine and other deoxycytidine analogues. Antimicrob. Agents Chemother. 51:XXX. [PMC free article] [PubMed]
3. Blaise, P., P. Clevenbergh, D. Vaira, M. Moutschen, and P. Dellamonica. 2002. HIV resistance to antiretroviral drugs: mechanisms, genotypic and phenotypic resistance testing in clinical practice. Acta Clin. Belg. 57:191-201. [PubMed]
4. Cahn, P., I. Cassetti, R. Wood, P. Phanuphak, L. Shiveley, R. C. Bethell, and J. Sawyer. 2006. Efficacy and tolerability of 10-day monotherapy with apricitabine in antiretroviral-naive, HIV-infected patients. AIDS 20:1261-1268. [PubMed]
4a. Cohen, C., C. Katiama, R. Murphy, J. Gathe, C. Brinson, G. Richmond, P.-M. Girard, J. Fessel, A. Liappis, E. Puglia, B. Rodwick, J. Nadler, W. O'Brien, K. Arasteh, M. Otto, S. Erickson-Viitanen, and R. Levy. 2005. Abstr. Third Int. AIDS Soc. Conf. HIV Pathog. Treat., abstr. WeOaLB0103, 2005.
5. de Muys, J. M., H. Gourdeau, N. Nguyen-Ba, D. L. Taylor, P. S. Ahmed, T. Mansour, C. Locas, N. Richard, M. A. Wainberg, and R. F. Rando. 1999. Anti-human immunodeficiency virus type 1 activity, intracellular metabolism, and pharmacokinetic evaluation of 2′-deoxy-3′-oxa-4′-thiocytidine. Antimicrob. Agents Chemother. 43:1835-1844. [PMC free article] [PubMed]
6. Havlir, D. V., C. Tierney, G. H. Friedland, R. B. Pollard, L. Smeaton, J. P. Sommadossi, L. Fox, H. Kessler, K. H. Fife, and D. D. Richman. 2000. In vivo antagonism with zidovudine plus stavudine combination therapy. J. Infect. Dis. 182:321-325. [PubMed]
7. Ho, H. T., and M. J. Hitchcock. 1989. Cellular pharmacology of 2′,3′-dideoxy-2′,3′-didehydrothymidine, a nucleoside analog active against human immunodeficiency virus. Antimicrob. Agents Chemother. 33:844-849. [PMC free article] [PubMed]
8. Hoggard, P., S. Khoo, M. Barry, and D. Back. 1996. Intracellular metabolism of zidovudine and stavudine in combination. J. Infect. Dis. 174:671-672. [PubMed]
9. Hoggard, P. G., S. D. Sales, S. Kewn, D. Sunderland, S. H. Khoo, C. A. Hart, and D. J. Back. 2000. Correlation between intracellular pharmacological activation of nucleoside analogues and HIV suppression in vitro. Antivir. Chem. Chemother. 11:353-358. [PubMed]
10. Hoggard, P. G., S. Kewn, M. G. Barry, S. H. Khoo, and D. J. Back. 1997. Effects of drugs on 2′,3′-dideoxy-2′,3′-didehydrothymidine phosphorylation in vitro. Antimicrob. Agents Chemother. 41:1231-1236. [PMC free article] [PubMed]
11. Johnson, M. A., D. G. Johns, and A. Fridland. 1987. 2′,3′-Dideoxynucleoside phosphorylation by deoxycytidine kinase from normal human thymus extracts: activation of potential drugs for AIDS therapy. Biochem. Biophys. Res. Commun. 148:1252-1258. [PubMed]
12. Johnson, M. A., K. H. Moore, G. J. Yuen, A. Bye, and G. E. Pakes. 1999. Clinical pharmacokinetics of lamivudine. Clin. Pharmacokinet. 36:41-66. [PubMed]
13. Panel on Clinical Practices for Treatment of HIV Infection convened by the U.S. Department of Health and Human Services. 4 May 2006. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. [Online.] http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
14. Ray, A. S. 2005. Intracellular interactions between nucleos(t)ide inhibitors of HIV reverse transcriptase. AIDS Rev. 7:113-125. [PubMed]
15. Taylor, D. L., P. S. Ahmed, A. S. Tyms, L. J. Wood, L. A. Kelly, P. Chambers, J. Clarke, J. Bedard, T. L. Bowlin, and R. F. Rando. 2000. Drug resistance and drug combination features of the human immunodeficiency virus inhibitor, BCH-10652 [(+/−)-2′-deoxy-3′-oxa-4′-thiocytidine, dOTC]. Antivir. Chem. Chemother. 11:291-301. [PubMed]
16. Veal, G. J., M. G. Barry, S. H. Khoo, and D. J. Back. 1997. In vitro screening of nucleoside analog combinations for potential use in anti-HIV therapy. AIDS Res. Hum. Retrovir. 13:481-484. [PubMed]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)