HK1085921A - Use of a combination containing a non-nucleoside reverse transcriptase inhibitor (nnrti) with an inhibitor of cytochrome p450, such as protease inhibitors - Google Patents

Description

Use of compositions comprising non-nucleoside reverse transcriptase inhibitors (NNRTIs) and cytochrome P450 inhibitors such as protease inhibitors

Technical Field

The present invention relates to an improved method of treating HIV-1 infection using compounds of formula I.

Background

The compound of formula I is a non-nucleoside HIV-1 reverse transcriptase inhibitor, having the chemical name 5, 11-dihydro-11-ethyl-5-methyl-8- {2- { (1-oxido-4-quinolinyl) oxy } ethyl } -6H-bipyridino [3, 2-b:2 ', 3' -e ] [1, 4] diaza  -6-one and the structural formula:

us patent 6,420,359 describes the synthesis of compounds of formula I and their use for the treatment of HIV infection.

To date, little is known about the metabolism of the compound of formula I in humans, the effect this metabolism may have on the pharmacokinetics of the compound and, in turn, the practical utility as a drug.

Detailed Description

It has now been found that the compounds of formula I are rapidly metabolized under the influence of cytochrome P450, in particular the CYP3a4 isoform. The fact that the compounds of formula I can be rapidly metabolized by cytochrome P450 is not known before, but it is this fact that reveals a problem that has not been noticed so far: the rapid metabolism of the compound of formula I by cytochrome P450 makes it difficult to maintain therapeutically effective blood levels.

The present invention provides a method for solving the above newly found problems: we have found that by administering a cytochrome P450 inhibitor, particularly an inhibitor of CYP3a4, in combination with a compound of formula I, the pharmacokinetics of the compound of formula I can be significantly improved. We have also found that therapeutically effective blood levels of a compound of formula I can be readily obtained when the compound of formula I is administered in combination with an inhibitor of the cytochromes P450, especially an inhibitor of CYP3a 4. Inhibition of the enzymatic activity of cytochrome P450, and in particular CYP3a4, can be used to slow the metabolism of the compound of formula I and thus significantly improve its pharmacokinetics such that a small amount of the compound of formula I need be administered to achieve the desired therapeutic effect. Higher blood levels are also obtained.

Accordingly, the present invention provides an improved method of treating HIV-1 infection using compounds of formula I. In its broadest sense, the method comprises administering to a patient in need of treatment for HIV-1 infection, in combination, an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and an amount of at least one pharmaceutically acceptable inhibitor of cytochrome P450, especially CYP3a4, sufficient to significantly inhibit the enzymatic activity of cytochrome P450, especially CYP3a4, and thereby render the amount of the compound of formula I administered therapeutically effective. A therapeutic effect may be considered to be obtained when the rate of viral replication is reduced.

The present invention also provides a method of increasing the blood level of a compound of formula I in a human, comprising co-administering to a patient in need of treatment for HIV-1 infection an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and an amount of at least one pharmaceutically acceptable inhibitor of cytochrome P450, especially CYP3a4, sufficient to substantially inhibit the enzymatic activity of cytochrome P450, especially CYP3a4, and thereby inhibit the metabolism, enhance the action and prolong the duration of action of a compound of formula I.

Accordingly, the present invention provides the use of a combination as described hereinbefore and hereinafter for the manufacture of a medicament for improving the pharmacokinetics of the compound of formula I.

Furthermore, the present invention provides the use of a pharmaceutical combination as described above and below for the preparation of a medicament for increasing the blood level of a compound of the formula I in humans.

In addition, the present invention provides a pharmaceutical combination of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and an amount of an inhibitor of the cytochromes P450 effective to improve the pharmacokinetics of the compound of formula I.

The invention also provides a pharmaceutical composition comprising a pharmaceutical combination as described above and below and a pharmaceutically acceptable carrier.

In addition, the present invention provides a kit of parts comprising a pharmaceutical combination as described herein before and below, the kit of parts being characterized as follows:

(a) a first container containing a compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, and

(b) the second container contains an inhibitor of cytochrome P450 and at least one pharmaceutically acceptable carrier.

The invention also provides a method of preventing or treating HIV infection in a human, which method comprises co-administering to a human in need of such treatment a combination as described hereinbefore and hereinafter.

Thus, the present invention also provides the use of a pharmaceutical combination as described above and below for the manufacture of a medicament for the prevention or treatment of HIV infection in a human.

In addition, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament comprising a pharmaceutical combination as described above and below for the prevention or treatment of HIV infection in a human.

The invention also provides the use of an inhibitor of the cytochromes P450 in the manufacture of a medicament comprising a combination as described hereinbefore and hereinafter for the prophylaxis or treatment of HIV infection in a human.

In addition, the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in combination with an inhibitor of cytochrome P450 for the prevention or treatment of HIV infection in a human.

Accordingly, the present invention also provides the use of an inhibitor of cytochrome P450 for the manufacture of a medicament for use in combination with a compound of formula I or a pharmaceutically acceptable salt thereof for the prevention or treatment of HIV infection in a human.

In the context of the present invention, it is preferred to inhibit the enzymatic activity of cytochrome P450, in particular CYP3a4, such that the enzymatic activity is at least halved. However, in order to obtain the greatest possible pharmacokinetic improvement, it is more preferred to inhibit substantially all of this enzyme activity.

The term "pharmaceutically acceptable" as used herein refers to a property and/or substance that is acceptable to a patient from a pharmacological/toxicological point of view and to a pharmacist for the preparation of a medicament from a physical/chemical point of view in terms of composition, formulation (formulation), stability, patient tolerability and bioavailability.

The term "cytochrome P450 inhibitor" or "CYP 3a4 inhibitor" or "CYP 450 inhibitor" as used herein refers to any member of a class of drugs and/or natural products that are capable of inhibiting at least the CYP3a4 isoform of cytochrome P450. Such pharmaceutical and/or natural products include, but are not limited to, amprenavir (amprenavir), atazanavir, clarithromycin (clarithromycin), cyclosporin (cyclosporine), diltiazem (diltiazem), erythromycin (erythromycin), itraconazole (itraconazole), indoxacvir (indinavir), ketoconazole (ketoconazole), mifeprradil, nefazodone (nefazodone), nelfinavir (nelfinavir), ritonavir (ritonavir), vitamin E, bergamottin (bergamottin), dihydrobergamottin (dihydoxybergamottin), and grapefruit juice (grapefruit juice). See GK Dresser et al clin pharmaceuticals 2000 Jan; 38(1): 41-57 for a review of clinically relevant CYP3A4 inhibitors. In the context of the present invention, a preferred CYP3a4 inhibitor is ritonavir.

The term "treatment" as used herein means the combined or alternating administration of the compounds of the invention having antiviral activity according to the methods of the invention to reduce or eliminate symptoms of viral infection and/or to reduce the amount of viral load in a patient.

The term "prevent" or "prevention" as used herein means the combined or alternating administration of a compound of the invention having antiviral activity to an individual who has been exposed to a virus but has not yet developed a related condition and/or has not detected the presence of a virus in the blood, according to the methods of the invention. The term "preventing" or "prophylaxis" includes treatment of the mother immediately prior to parturition (i.e., immediately prior to parturition) and optionally during lactation to block transmission from mother to baby.

It is possible to practice the invention by administering one or more CYP450 inhibitors. The present invention encompasses these two different scenarios.

The term "co-administration" as used in the context of the present invention refers to the administration of a compound of formula I or a pharmaceutically acceptable salt thereof and one or more CYP450 inhibitors within a period not exceeding 24 hours apart. These drugs may be administered separately in separate dosage forms or they may be combined into a single dosage form.

Thus, the pharmaceutical combination of the present invention may comprise a single composition formulated from a compound of formula I or a pharmaceutically acceptable salt thereof and an inhibitor of cytochrome P450 or separate compositions.

An example of a separate composition is a kit component comprising:

(a) a first container containing a compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, and

(b) a second container comprising an inhibitor of cytochrome P450 and at least one pharmaceutically acceptable carrier.

In the context of the pharmaceutical combinations, methods and uses described in the present invention, the preferred amount of a compound of formula I or a pharmaceutically acceptable salt thereof is a therapeutically effective amount. A "therapeutically effective amount" herein is to be understood in the context of the present invention (i.e. when a compound of formula I is administered in combination with a cytochrome P450 inhibitor). Preferred amounts of a compound of formula I or a pharmaceutically acceptable salt thereof are in the range of 50mg to 3000mg, especially in the range of 50mg to 500mg, most preferably in the range of 50mg to 300 mg. Especially an amount ranging from 100mg to 300mg is most preferred.

In the context of the pharmaceutical combinations, methods and uses according to the invention, the preferred amount of the cytochrome P450 inhibitor is an amount which results in an improved pharmacokinetics of the compound of the formula I. In the context of the present invention, the pharmacokinetics of the compound of formula I is considered to be improved when the plasma level of the compound of formula I is increased, the effect is enhanced or the lifetime is prolonged compared to when the compound of formula I is administered without the co-administration of the inhibitor of the cytochromes P450. Alternatively, in the context of the present invention, the pharmacokinetics of the compound of formula I may be considered to be improved when the metabolism of the compound of formula I by cytochrome P450 is reduced, preferably at least reduced 1/3, more preferably at least reduced 1/2, most preferably at least reduced 2/3, as compared to when the compound of formula I is administered without the administration of a cytochrome P450 inhibitor in combination.

Further, preferred amounts of the inhibitor of the cytochromes P450 are those amounts which result in a reduction, preferably a halving, of the enzymatic activity of the cytochromes P450, especially the CYP3a4 isoform in order to improve the pharmacokinetics of the compound of the formula I. Most preferably, the amount is selected to inhibit substantially all of the enzyme activity to obtain the greatest possible pharmacokinetic improvement.

In one example where ritonavir or a pharmaceutically acceptable salt thereof is selected as the inhibitor of cytochrome P450, a preferred amount of the compound of formula I or salt thereof is in the range of 30mg to 1000mg, more preferably in the range of 30mg to 500mg, and most preferably in the range of 30mg to 300 mg. Especially the range of 30mg to 200mg is most preferred.

U.S. patent 6,420,359 describes processes for preparing compounds of formula I, pharmaceutical compositions containing compounds of formula I and their use in the treatment of HIV-1 infection.

In examples 1 and 2 below it is described that the administration of a compound of formula I in combination with a sub-therapeutic dose of ritonavir increases the amount and duration of plasma levels of the compound of formula I. Although the administration of ritonavir in combination with the compound of formula I results in low blood levels of ritonavir, this results in a large increase in plasma levels of the compound of formula I such that a lower dose of the compound of formula I results in a better therapeutic effect than a much higher dose of the compound of formula I administered alone. This is a result of both increasing the plasma levels of the compound of formula I and retarding the elimination of the compound of formula I.

PCT patent application No. WO94/14436, 7/1994, and U.S. patent application Ser. No.08/469,965, 6/1995, published on 7/1994, describe a process for the preparation of ritonavir ((2S, 3S, 5S) -5- (N- (N- ((N-methyl-N- ((2-isopropyl-4-thiazolyl) methyl) amino) carbonyl) -L-valyl) amino) -2- (N- ((5-thiazolyl) methoxycarbonyl) amino) -1, 6-diphenyl-3-hydroxyhexane).

The compounds of formula I and cytochrome P450 inhibitors useful in the methods of the invention may be in free form or in a form protected at one or more of the remaining (previously unprotected) carboxyl, amino, hydroxyl, or other reactive groups. The protecting group may be any protecting group known in the art. T.w.greene, Protecting Groups in Organic Synthesis, Wiley, n.y., (1981); McOmie, ed.protective Groups in Organic Chemistry, Plenum Press (1973); examples of protecting groups for nitrogen and oxygen are disclosed in J.Fuhrhop and G.Benzlin, Organic Synthesis, Verlag Chemie (1983). The nitrogen protecting group includes t-Butoxycarbonyl (BOC), benzyloxycarbonyl (benzyloxycarbonyl), acetyl (acetyl), allyl (allyl), phthalyl (phenyl), benzyl (benzyl), benzoyl (benzoyl), trityl (trityl) and the like.

The methods described herein provide for the use of pharmacologically acceptable salts and/or hydrates of the compounds of formula I and inhibitors of cytochrome P450. A pharmacologically acceptable salt is one which is readily known by the pharmaceutical chemist to be significantly equivalent to the parent compound in terms of properties such as formulation (formulation), stability, patient acceptability and bioavailability. The salts of the cytochrome P450 inhibitor and the compound of formula I may include disalts, such as disodium, dipotassium, dicalcium salts, with disodium salts being most preferred.

The methods of the present invention are useful for treating patients infected with human immunodeficiency virus strain 1(HIV-1), which leads to acquired immunodeficiency syndrome (AIDS) and related diseases. For this purpose, the compound of formula I and ritonavir may be administered by oral, intranasal, transdermal, subcutaneous and parenteral (including intramuscular and intravenous) routes in the following dosages.

Although the range of cytochrome P450 inhibitors that can be used in the present invention is wide, as mentioned above, ritonavir is the preferred inhibitor. Thus, the invention will be further elucidated by an assay describing in detail how to administer a compound of formula I in combination with ritonavir.

A sub-therapeutic dose of ritonavir of 100mg was administered 12 hours prior to, and at the time of, administration of the compound of formula I to study the drug-drug clinical interaction between ritonavir and the compound of formula I. It has been found that the dosage of ritonavir has a significant substantial effect in increasing plasma levels of the compound of formula I, enhancing its effect or prolonging its lifetime. Alternatively, the plasma level of a compound of formula I can be varied by varying its dose, but not its time of existence in plasma. These results show that target plasma levels of the compound of formula I can be achieved and maintained by different but defined dose combinations of ritonavir. This pharmacokinetic drug interaction is of potentially great clinical importance for reasons including:

■ the compound of formula I has stronger antiviral activity, because the antiviral activity is dependent on the level and duration of the drug in blood plasma;

■ the possibility of reducing the dosage of the compound of formula I administered, which may improve patient compliance with antiviral therapy (compliance);

■ safety may be improved because less of the compound of formula I is required to achieve the desired antiviral effect.

The lowest dose of ritonavir tested was administered at 100mg twice daily, which was chosen because it is the only tablet strength (tablet strength) available for ritonavir on the market. At such dosage levels, ritonavir can increase plasma levels of the compound of formula I by almost 40-fold as evidenced by the measurement of the area under the curve.

The half-life of a single dose of the compound of formula I of 1-100mg in the absence of ritonavir is approximately 2 hours, which makes its clinical use suboptimal. The half-life of the compound of formula I is extended to 15 hours when administered in combination with 100mg of ritonavir, which makes the compound of formula I and low dose of ritonavir a very attractive drug combination for the treatment of AIDS.

Those skilled in the art will be familiar with how to formulate the compounds of the invention into appropriate pharmaceutical dosage forms. Examples of dosage forms include oral dosage forms such as tablets or capsules, or parenteral dosage forms such as sterile solutions.

Both solid and liquid dosage forms can be prepared for oral administration. Solid compositions may be prepared by mixing a compound of the invention with conventional ingredients such as talc (tallc), magnesium stearate, dicalcium phosphate, magnesium aluminum silicates, calcium sulfate, starch, lactose, gum arabic (acacia), methyl cellulose, or functionally similar pharmaceutical diluents and carriers. Capsules are prepared by mixing a compound of the invention with an inert pharmaceutical diluent and placing the mixture in hard gelatin capsules of suitable size. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound of the present invention with an acceptable inert oil such as vegetable oil or light liquid petrolatum. Slurries are prepared by dissolving the compounds of the present invention in an aqueous medium and adding sugar, aromatic flavoring agents and preservatives. Elixirs (Elixirs) are prepared by using a hydroalcoholic vehicle (e.g. ethanol), a suitable sweetening agent such as sugar or saccharin and an aromatic flavoring agent. Suspensions are prepared by using an aqueous medium and a suspending agent such as gum arabic, tragacanth gum or methyl cellulose.

The increased bioavailability is accompanied by an increase in half-life, which has the potential to effectively reduce the number of required dosage units of the compound of formula I, which can be reduced by a factor of 30.

Parenteral administration of the compounds of the invention may be by injection or intravenous infusion. Solutions for parenteral administration are prepared by dissolving the compound of the invention in an aqueous medium and filter-sterilizing the resulting solution in a sealable vial or ampoule. Parenteral suspensions are prepared in essentially the same manner as parenteral solutions, except that sterile suspending media are used and the compounds of the invention are sterilized with ethylene oxide or a suitable gas and suspended in such media.

The exact route of administration, dosage, or frequency of administration will be readily determined by those skilled in the art, and will depend on the particular age, weight, general physical condition, or other clinical symptoms of the patient being treated.

Having generally described the invention, the same will be more readily understood through reference to the following examples. These examples are provided to illustrate the invention and are not to be construed as limiting the invention.

Examples

Pharmacokinetic drug-drug interaction of a Compound of formula I and ritonavir

Materials and methods：

Single agent, single treatment groups were studied to evaluate the potential pharmacokinetic drug-drug interaction between the protease inhibitor compound of formula I and ritonavir. The compound of formula I is administered as a solution containing 5mg or 12.5mg of the compound of formula I and excipients, and ritonavir is used as 100mg of the commercial product (Norvir) which is administered 12 hours prior to, and at the time of, administration of the compound of formula I. Baseline pharmacokinetic data were obtained for compounds of formula I up to a single 100mg dose. The drugs administered in combination were compared to baseline values. Healthy volunteers were used for this study. Pharmacokinetic analyses were performed based on the results obtained in these studies.

Pharmacokinetic and statistical methods

Pharmacokinetic parameters such as AUC, Cmax, tmax, oral clearance (oral clearance) and terminal half-life (terminal half-life) were determined using standard non-compartmental (noncromoplantal) techniques.

Results：

Effect of ritonavir on Compounds of formula I：

Table 1 and figure 1 show the mean (SD) plasma concentrations of the compound of formula I after administration of the compound of formula I alone, and in combination with Ritonavir (RTV). Table 2 provides pharmacokinetic estimates of the compounds of formula I up to 100mg oral dose. The mean Cmax value for the compound of formula I increased approximately 5-6 fold in the presence of ritonavir, while the mean AUC value for the compound of formula I increased nearly 40 fold due to its half-life extending from 2 hours to 15 hours (as shown in figure 1).

Discussion of the related Art：

The results of this study reveal substantial pharmacokinetic interactions involving both the compound of formula I and ritonavir. It was shown that ritonavir both inhibits metabolism of drugs that are substrates for cytochrome P4503A (CYP3A) (CYP3A is the major P450 isoform of the I stage metabolism of the compound of formula I) and affects its uptake via P-glycoprotein inhibition. Similarly, plasma ritonavir levels are also reduced by compounds known to induce metabolism (e.g., rifampin).

Lower doses of ritonavir than those used in this study are expected to be sufficient to substantially increase the plasma levels of the compound of formula I.

Table 1: effect of ritonavir on the pharmacokinetics of the Compound of formula I

PK parameters	Compound of formula I + RTV		Compounds of formula I only
						Average	SD	Average	SD
5mg+RTV
					AUC 0-t(hr*ng/mL)	577.83	121.14	13.56	10.13
Cmax(ng/mL)	22.79	3.70	3.64	2.23
					Tmax(hr)	4.00	1.63	1.50	0.71
Half-life (hr)	15.30	3.25	-*	-
					12.5mg+RTV
AUC 0-t(hr*ng/mL)	1703.6	332.6	57.1	60.8
					Cmax(ng/mL)	74.11	14.56	14.82	14.42
Tmax(hr)	3.59	2.42	1.0	0
					Half-life (hr)	15.89	3.32	4.10	1.91

^*Insufficient data, the above experiments were limited to a specified half-life

Table 2: pharmacokinetics of Compounds of formula I alone

Dosage form		Cmax Tmax AUC half-life CL/F% as unchanged drug (ng/mL) (hr)*ng/mL) (hr) (mL/min) percent cleared by the kidneys
			12.5mg	Mean SD	14.82 1.00 63.15 4.10 243495.99 0.2114.42 0.00 68.30 1.91 118873.29 0.12
25mg	Mean SD	41.63 0.83 139.36 3.44 200752.61 0.4129.09 0.26 71.41 1.38 80507.44 0.32
			50mg	Mean SD	163.81 0.67 437.37 2.50 124815.56 0.4839.97 0.26 122.40 0.27 39809.58 0.30
75mg	Mean SD	347.68 0.67 816.70 2.21 263277.68 0.60222.74 0.26 550.20 0.26 400589.38 0.43
			100mg	Mean SD	937.23 0.55 1385.01 1.86 75634.54 0.81141.66 0.21 277.01 0.24 15029.80 0.56

Claims (25)

1. A pharmaceutical combination of a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and an amount of a cytochrome P450 inhibitor effective to improve the pharmacokinetics of the compound of formula I.

2. A pharmaceutical combination according to claim 1, characterized in that the inhibitor of the cytochromes P450 is an inhibitor of CYP 3A.

3. A pharmaceutical combination according to claim 2, characterized in that the inhibitor of the cytochromes P450 is selected from the group consisting of amprenavir, atazanavir, clarithromycin, cyclosporin, diltiazem, erythromycin, itraconazole, indinavir, ketoconazole, mifepril, nefazodone, nelfinavir, ritonavir, vitamin E, bergamottin, dihydroxybergamottin and grapefruit juice.

4. A combination according to claim 3, characterized in that the inhibitor of the cytochromes P450 is ritonavir or a pharmaceutically acceptable salt thereof.

5. Pharmaceutical combination according to one or more of the preceding claims, characterized in that the amount of the compound of the formula I or of the pharmaceutically acceptable salt thereof is between 50mg and 3000 mg.

6. Pharmaceutical combination according to claim 4 or 5, characterized in that the amount of ritonavir or a pharmaceutically acceptable salt thereof is from 30mg to 500 mg.

7. Pharmaceutical combination according to one or more of claims 1 to 6, characterized in that the compound of formula I or a pharmaceutically acceptable salt thereof and the inhibitor of the cytochromes P450 are formulated as a single composition.

8. Pharmaceutical combination according to one or more of claims 1 to 6, characterized in that the compound of the formula I or a pharmaceutically acceptable salt thereof and the inhibitor of the cytochromes P450 are formulated separately in different compositions.

9. A pharmaceutical composition comprising a pharmaceutical combination according to one or more of claims 1 to 8 and at least one pharmaceutically acceptable carrier.

10. A kit of parts comprising a pharmaceutical combination according to one or more of claims 1 to 8, characterized in that:

(a) a first container containing a compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, and

(b) the second container contains an inhibitor of cytochrome P450 and at least one pharmaceutically acceptable carrier.

11. A method for the prophylaxis or treatment of HIV infection in a human, which comprises co-administering to a human in need of such treatment a pharmaceutical combination according to one or more of claims 1 to 8.

12. Use of a pharmaceutical combination according to one or more of claims 1 to 8 for the preparation of a medicament for the prophylaxis or treatment of HIV infection in a human.

13. Use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament comprising a pharmaceutical combination according to one or more of claims 1 to 8 for the prevention or treatment of HIV infection in a human.

14. Use of an inhibitor of the cytochromes P450 in the manufacture of a medicament comprising a pharmaceutical combination according to one or more of claims 1 to 8 for the prophylaxis or treatment of HIV infection in a human.

15. Use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in combination with an inhibitor of the cytochromes P450 for the prevention or treatment of HIV infection in a human.

16. Use of an inhibitor of cytochrome P450 in the manufacture of a medicament for use in combination with a compound of formula I or a pharmaceutically acceptable salt thereof for the prevention or treatment of HIV infection in a human.

17. A method for improving the pharmacokinetics of the compound of formula I, comprising co-administering to a human in need of such treatment a pharmaceutical combination according to one or more of claims 1 to 8.

18. Use of a pharmaceutical combination according to one or more of claims 1 to 8 for the preparation of a medicament for improving the pharmacokinetics of the compound of the formula I.

19. A method for increasing the human blood levels of a compound of formula I, which comprises co-administering to a human in need of such treatment a pharmaceutical combination according to one or more of claims 1 to 8.

20. Use of a pharmaceutical combination according to one or more of claims 1 to 8 for the preparation of a medicament for increasing the human blood levels of a compound of formula I.

21. A method of treating HIV-1 infection in a human infected with HIV-1, the method comprising administering a compound of formula I in combination with one or more CYP450 inhibitors in an amount sufficient to reduce metabolism of the compound of formula I by CYP450 by at least half.

22. The method of claim 21, wherein the amount of the compound of formula I administered is therapeutically effective by co-administration of one or more CYP450 inhibitors.

23. The method of claim 21, wherein metabolism of the administered compound of formula I via CYP450 is reduced by at least half as a result of co-administration of the CYP450 inhibitor.

24. The method of claim 21, 22 or 23, wherein the CYP450 inhibitor is selected from the group consisting of amprenavir, atazanavir, clarithromycin, cyclosporine, diltiazem, erythromycin, itraconazole, indinavir, ketoconazole, mifeprazole, nefazodone, nelfinavir, ritonavir, vitamin E, bergamottin, dihydroxybergamottin, and grapefruit juice.

25. The method of claim 21, 22 or 23, wherein the CYP450 inhibitor is ritonavir.